PIER GIUSEPPE DE BENEDETTI - personale UniMoRe

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PIER GIUSEPPE DE BENEDETTI

Docente a contratto
Dipartimento di Scienze della Vita sede ex-Chimica

Pubblicazioni

2018 - Computational modeling approaches to quantitative structure–binding kinetics relationships in drug discovery [Articolo su rivista]
De Benedetti, Pier G.; Fanelli, Francesca
abstract

Simple comparative correlation analyses and quantitative structure–kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug–target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling.

2014 - Multiscale quantum chemical approaches to QSAR modeling and drug design [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

The comparative use of classical, quantum chemical (QC) ligand-based (LB) and structure-based (SB) quantitative structure-activity relationship (QSAR) results in a detailed and mechanistic-causative description, at different scales (multiscale: classical=macroscopic, LB and SB=electronic-atomistic-nanoscale) and resolution levels, of the energetics and thermodynamics of the binding event for a congeneric set of ligands and/or drugs. QC interaction propensity (reactivity) descriptors in LB QSARs provide an implicitly more accurate estimation of the enthalpic contribution to ligand-target interactions compared with classical QSAR. As for QSAR models from ab initio SB fragment molecular orbital calculations, an explicit enthalpic description of the different additive terms in the computed binding energy is obtainable. Moreover, it is possible to estimate the difference in the free energy change of the ligand-target complex formation and evaluate, on a correlative basis, the contribution of each additive free energy term to the total value.

2013 - Protonation States and Conformational Dynamics in Ligand-Target Recognition and Binding [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe
abstract

The correct chemical approach to molecular recognition and ligand binding (small molecules, drugs, and bio-molecules) to target biomolecules requires, in principle, the evaluation of the prototropic and conformational equilibria between the different protonation states (acidic, basic, and tautomeric) and conformers. These equilibria depend on the environment and on the target structural features (prototropic forms, conformational flexibility, folding/unfolding, etc.). Thus, prototropic and conformational ensembles of both ligands and targets are strictly interdependent and control molecular recognition and binding events in many bioprocesses. In this CPD issue some of the more representative approaches and applications presented by leading scientists in the field are collected in an attempt to illustrate the roles of prototropic and conformational ensembles of the interacting partners in molecular recognition, binding, information transfer, and functional responses.

2013 - Protonation States and Conformational Ensemble in Ligand-based QSAR Modeling [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe
abstract

Drug affinity and function depend on the different protonation species (present in the biological context) that generate different conformational ensembles with different structural features and, hence, different physico-chemical properties. In the present review article these strongly interdependent structural features will be considered for their crucial role in ligand-based QSAR modeling and drug design by using quantum chemical electronic/reactivity descriptors and molecular shape description. Some selected and relevant examples illustrate the role of these molecular descriptors, computed on the bioactive protonation states and conformers, as determinant factors in mechanistic/causative QSAR analysis.

2011 - Update 1 of: Computational Modeling Approaches to Structure-Function Analysis of G Protein-Coupled Receptors [Articolo su rivista]
Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Not available

2010 - Computational quantum chemistry and adaptive ligand modeling in mechanistic QSAR [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

Drugs are adaptive molecules. They realize this peculiarity by generating different ensembles of prototropic forms and conformers that depend on the environment. Among the impressive amount of available computational drug discovery technologies, quantitative structure-activity relationship approaches that rely on computational quantum chemistry descriptors are the most appropriate to model adaptive drugs. Indeed, computational quantum chemistry descriptors are able to account for the variation of the intramolecular interactions of the training compounds, which reflect their adaptive intermolecular interaction propensities. This enables the development of causative, interpretive and reasonably predictive quantitative structure-activity relationship models, and, hence, sound chemical information finalized to drug design and discovery.

2009 - Computational modeling of intramolecular and intermolecular communication in GPCRs [Articolo su rivista]
Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe; Raimondi, Francesco; M., Seeber
abstract

Intramolecular and intermolecular communication is a privileged issue in G protein-Coupled Receptor (GPCR) function as the prominent role of these receptors is to respond to extracellular signals by catalyzing nucleotide exchange in intracellular G proteins. In the last decade or so we have applied much effort in elaborating computational strategies to infer the mechanisms of intramolecular and intermolecular communication in a number of GPCRs of the rhodopsin family. In this article, we review the most relevant achievements on the matter. In summary, the receptor sites of activating mutations or ligand-binding communicate with a common allosteric site in the cytosolic domains. This was inferred from the observation that local perturbations by activating mutations or ligands correlate with increases in solvent accessibility of the neighborhoods of the highly conserved E/DRY receptor motif. The latter turned out to be the primary recognition point for the C-terminus of the G protein alpha-subunit, independent of the receptor or the G protein type. In spite of the highly composite nature of the receptor-G protein interface, receptor contacts with the C-terminus of the alpha5-helix seem to be the major players in the receptor-catalyzed formation of a nucleotide exit route. The latter would lie in between the alphaF-helix and the beta6/alpha5 loop, which detach from each other upon receptor binding, giving solvent accessibility to the nucleotide. A worthy inference of the studies is that GPCRs employ common pathways for the transfer of functionally relevant information.

2009 - Intra- and intermolecular communications in proteins. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe
abstract

No available

2009 - Ligand-Receptor Communication and Drug Design [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

Ligand-protein and protein-protein interactions play a pivotal role in any cellular process and function by means of complex and dynamic mechanisms that involve sophisticated intra- and intermolecular communication pathways. The deeper understanding of the molecular and structural mechanisms of these pathways of chemical information transfer constitutes the foundations of rational druggable target discovery and drug design. In this context the role of both molecular recognition/communication between the interacting partners and their quantitative/dynamic description constitute the crucial point. In this respect, many approaches at different level of complexity have been developed and applied to different druggable target like enzymes, membrane receptors and protein assembly. They mainly differ in the accuracy and resolution level of molecular description and, hence, in the derived quantitative molecular descriptors/predictors and ligand-target models. In this review, we will try to illustrate some selected examples of ligand-target receptor protein models, by comparatively considering both series of ligands (ligand-based communication modeling) and ligand-target complexes (target-based communication modeling) in order to describe the relevant structural/dynamic features of chemical information transfer in the ligand/drug design endeavour.

2008 - Computational modeling of selective pharmacophores at the alpha1-adrenergic receptors [Capitolo/Saggio]
Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

1. Introduction2. Ligand-based and receptor-based pharmacophore modeling and QSAR analysis3. The general 1-AR pharmacophore3.1. Ligand-based pharmacophore and virtual screening 3.1.1. Prazosin analogues (2,4-diamino-6,7-dimethoxyquinazoline derivatives)3.1.2. 1,4-benzodioxan (WB-4101) related compounds3.1.3. Arylpiperazine derivatives4. Modeling the 1-AR subtype selectivities of different antagonist classes4.1.1. Supermolecule based subtype pharmacophore and QSAR models4.1.2. Ligand based subtype pharmacophores4.1.3. Receptor-based subtype pharmacophore and ligand-target/antitarget interaction-based QSAR5. Antitarget modeling of biogenic amine-binding GPCRs 6. Inverse agonism: an alternative way to interpret the 1a/1b-selectivity issue6.1 In vitro functional screening of 1a and 1b ligands.6.2 Ligand- and receptor-based structural interpretation of inverse agonism67. Concluding remarks 67.1. From molecules to pharmacophores to descriptors to models 78. Perspectives8.1. Multiscale computational modeling of GPCRs8.2. Molecular systems biology and pharmacology: “network drugs”

2008 - Mechanisms of inter- and intramolecular communication in GPCRs and G proteins [Articolo su rivista]
Raimondi, F; Seeber, M; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

This study represents the first attempt to couple, by computational experiments, the mechanisms of intramolecular and intermolecular communication concerning a guanidine nucleotide exchange factor (GEF), the thromboxane A2 receptor (TXA2R), and the cognate G protein (Gq) in its heterotrimeric GDP-bound state. Two-way pathways mediate the communication between the receptor-G protein interface and both the agonist binding site of the receptor and the nucleotide binding site of the G protein. The increase in solvent accessibility in the neighborhoods of the highly conserved E/DRY receptor motif, in response to agonist binding, is instrumental in favoring the penetration of the C-terminus of Gqalpha in between the cytosolic ends of H3, H5, and H6. The arginine of the E/DRY motif is predicted to be an important mediator of the intramolecular and intermolecular communication involving the TXA2R. The receptor-G protein interface is predicted to involve multiple regions from the receptor and the G protein alpha-subunit. However, receptor contacts with the C-terminus of the alpha5-helix seem to be the major players in the receptor-catalyzed motion of the alpha-helical domain with respect to the Ras-like domain and in the formation of a nucleotide exit route in between the alphaF-helix and beta6/alpha5 loop of Gqalpha. The inferences from this study are of wide interest, as they are expected to apply to the whole rhodopsin family, given also the considerable G protein promiscuity.

2008 - Quantitative structure-activity relationship analysis of canonical inhibitors of serine proteases [Articolo su rivista]
Dell'Orco, D; DE BENEDETTI, Pier Giuseppe
abstract

Correlation analysis was carried out between binding affinity data values from the literature and physicochemical molecular descriptors of two series of single point mutated canonical inhibitors of serine proteases, namely bovine pancreatic trypsin inhibitor (BPTI) and turkey ovomucoid third domain (OMTKY3), toward seven enzymes. Simple quantitative structure-activity relationship (QSAR) models based on either single or double linear regressions (SLR or DLR) were obtained, which highlight the role of hydrophobic and bulk/polarizability features of mutated amino acids of the inhibitors in modulating both affinity and specificity. The utility of the QSAR paradigm applied to the analysis of mutagenesis data was underlined, resulting in a simple tool to quantitatively help deciphering structure-function/activity relationships (SFAR) of different protein systems.

2007 - In silico screening of mutational effects on enzyme-proteic inhibitor affinity: A docking-based approach [Articolo su rivista]
D., Dell'Orco; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

BACKGROUND: Molecular recognition between enzymes and proteic inhibitors is crucial for normal functioning of many biological pathways. Mutations in either the enzyme or the inhibitor protein often lead to a modulation of the binding affinity with no major alterations in the 3D structure of the complex. RESULTS: In this study, a rigid body docking-based approach has been successfully probed in its ability to predict the effects of single and multiple point mutations on the binding energetics in three enzyme-proteic inhibitor systems. The only requirement of the approach is an accurate structural model of the complex between the wild type forms of the interacting proteins, with the assumption that the architecture of the mutated complexes is almost the same as that of the wild type and no major conformational changes occur upon binding. The method was applied to 23 variants of the ribonuclease inhibitor-angiogenin complex, to 15 variants of the barnase-barstar complex, and to 8 variants of the bovine pancreatic trypsin inhibitor-beta Trypsin system, leading to thermodynamic and kinetic estimates consistent with in vitro data. Furthermore, simulations with and without explicit water molecules at the protein-protein interface suggested that they should be included in the simulations only when their positions are well defined both in the wild type and in the mutants and they result to be relevant for the modulation of mutational effects on the association process. CONCLUSION: The correlative models built in this study allow for predictions of mutational effects on the thermodynamics and kinetics of association of three substantially different systems, and represent important extensions of our computational approach to cases in which it is not possible to estimate the absolute free energies. Moreover, this study is the first example in the literature of an extensive evaluation of the correlative weights of the single components of the ZDOCK score on the thermodynamics and kinetics of binding of protein mutants compared to the native state.Finally, the results of this study corroborate and extend a previously developed quantitative model for in silico predictions of absolute protein-protein binding affinities spanning a wide range of values, i.e. from -10 up to -21 kcal/mol. The computational approach is simple and fast and can be used for structure-based design of protein-protein complexes and for in silico screening of mutational effects on protein-protein recognition.

2007 - In silico screening of mutational effects on transmembrane helix dimerization: insights from rigid-body docking and molecular dynamics simulations [Articolo su rivista]
D., Dell'Orco; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

In this study, a docking-based protocol has been probed for its ability to predict the effects of 32 single and double mutations on glycophorin A (GpA) homodimerization. Rigid-body docking simulations have been paralleled by molecular dynamics (MD) simulations in implicit membrane. The rigid-body docking-based approach proved effective in reconstituting the native architecture of the GpA dimer for the wild type and the wild-type-like mutants. The good correlative models between the intermolecular interaction descriptors derived both by rigid-body docking simulations and by MD simulations and experimental relative free energies support the assumption that the mutation-induced changes in the association free energy of GpA helices are essentially ascribed to differences in the packing interactions, whereas almost all the variations in the entropic contributions to the association free energy are constant and/or negligible. The MD-based models achieved provide insights into the structural determinants for disruptive and restoring mutational effects. The computational approaches presented in this study are fast and effective, and constitute simple and promising tools for in silico screening of mutational effects on the association properties of integral membrane proteins.

2006 - Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling [Articolo su rivista]
Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Herein we make an overview of the results of our computational experiments aimed at gaining insight into the molecular mechanisms of GPCR functioning either in their normal conditions or when hit by gain-of-function or loss-of-function mutations. Molecular simulations of a number of GPCRs in their wild type and mutated as well as free and ligand-bound forms were instrumental in inferring the structural features, which differentiate the mutation- and ligand-induced active from the inactive states. These features essentially reside in the interaction pattern of the E/DRY arginine and in the degree of solvent exposure of selected cytosolic domains. Indeed, the active states differ from the inactive ones in the weakening of the interactions made by the highly conserved arginine and in the increase in solvent accessibility of the cytosolic interface between helices 3 and 6. Where possible, the structural hallmarks of the active and inactive receptor states are translated into molecular descriptors useful for in silico functional screening of novel receptor mutants or ligands. Computational modeling of the supramolecular organization of GPCRs and their intracellular partners is the current challenge toward a deep understanding of their functioning mechanisms.

2006 - Single Amino Acid Contributions to Binding Affinity in Enzyme-Inhibitor Interactions: a Docking-Based Screening of BPTI-Beta Trypsin interaction [Capitolo/Saggio]
D., Dell'Orco; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

Enzyme-inhibitor interactions are crucial for normal functioning of many biological pathways. Point mutations in either the enzyme or the inhibitor molecule often lead to a modulation of the binding affinity (∆Go) with no major alterations in the 3D structure of the complex. The pos- sibility to screen in silico the effects of point mutations on ∆Go is of high interest, especially for protein design purposes. We have recently developed a computational protocol based on an existent rigid-body docking algorithm, which has shown a good capability to predict ∆Go changes upon mutations in protein-protein interactions. Here, we present the results obtained for the bovine pancreatic trypsin inhibitor (BPTI) and beta-Trypsin (β-Tryp) interaction. In this system, the BPTILys15 residue was replaced by eight different amino acids, hence varying the physico-chemical nature of the interface. The X-ray structure of each variant is available, as well as the effect of each substitution on the binding energetics. We compare our approach with data arising from both in vitro measurements and from another structure-based empirical approach, based on changes in solvent accessible surface areas (∆ASA) upon binding. The performance and the limitations of our approach are discussed.

2005 - Computational modeling approaches to Structure-Function Analysis of G Protein-Coupled Receptors [Articolo su rivista]
Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Not available

2005 - Probing fragment complementation by rigid-body docking: In silico reconstitution of calbindin D9k [Articolo su rivista]
D., Dell'Orco; M., Seeber; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Fragment complementation is gaining an increasing impact as a nonperturbing method to probe noncovalent interactions within protein supersecondary structures. In this study, the fast Fourier transform rigid-body docking algorithm ZDOCK has been employed for in silico reconstitution of the calcium binding protein calbindin D9k, from its two EF-hands subdomains, namely, EF1 (residues 1-43) and EF2 (residues 44-75). The EF1 fragment has been used both in its wild type and in nine mutant forms, in line with in vitro experiments. Consistent with in vitro data, ZDOCK reconstituted the proper fold of wild-type and mutated calbindin, locating the nativelike structures (i.e., holding a root-mean-square deviation < 1 A with respect to the X-ray structure) among the first 10 top-scored solutions out of 4000. Moreover, the three independent in silico reconstitutions of wild-type calbindin ranked a nativelike structure at the top of the output list, that is, the best scored one. The algorithm has been also successfully challenged in reconstituting the EF2 homodimer from two identical copies of the monomer. Furthermore, quantitative models consisting of linear correlations between thermodynamic data and ZDOCK scores were built, providing a tested tool for very fast in silico predictions of the free energy of association of protein-protein complexes solved at the atomic level and known to not undergo significant conformational changes upon binding.

2004 - Adenosine A(2A)-dopamine D-2 receptor-receptor heteromers. Targets for neuro-psychiatric disorders [Articolo su rivista]
S., Ferre; F., Ciruela; M., Canals; D., Marcellino; J., Burgueno; V., Casado; J., Hillion; M., Torvinen; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe; S. R., Goldberg; M., Bouvier; K., Fuxe; Agnati, Luigi Francesco; C., Lluis; R., Franco; A., Woods
abstract

Emerging evidence show; that G protein-coupled receptors can form homo- and heteromers. These include adenosine A(2A) receptor-dopamine D-2 receptor heteromers, which are most probably localized in the dendritic spines of the striatopallidal GABAergic neurons, where they are in a position to modulate glutamatergic neurotransmission. The discovery of A(2A) receptor-dopamine D-2 receptor heteromers gives a frame for the well-known antagonistic interaction between both receptors, which is the bases for a new therapeutic approach for neuropsychiatric disorders, such as Parkinson´s disease and schizoprenia. The present review deals mainly with the biochemical and molecular aspects of A(2A) receptor-dopamine D-2 receptor interactions. Recent results at the molecular level show that A(2A) receptor-dopamine D-2 receptor heteromers represent the first example of epitope-epitope electrostatic interaction underlying receptor heteromerization. Most probably A(2A) receptor-D-2 receptor heteromerization is not static, but subject to a dynamic regulation, related to the phosphorylation dependence of the A(2A) receptor epitope and to the ability of the D-2 receptor epitope to bind different partners. Finding out the mechanisms involved in this dynamic regulation can have important implications for the treatment of basal ganglia disorders, schizophrenia and drug addiction.

2004 - Design, Synthesis, Strucural Studies, Biological Evaluation, and Computational Simulations of Novel Potent AT1 Angiotensin II Receptor Antagonists Based on the 4-Phenylquinoline Structure [Articolo su rivista]
A., Cappelli; G. P., Mohr; A., Gallelli; M., Rizzo; M., Anzini; S., Vomero; L., Mennuni; F., Ferrari; F., Makovec; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; G., Giorgi
abstract

Novel AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties instead of theclassical biphenyl fragment were designed and synthesized as the first step of an investigationdevoted to the development of new antihypertensive agents and to the understanding of themolecular basis of their pharmacodynamic and pharmacokinetic properties. The newlysynthesized compounds were tested for their potential ability to displace [125I]Sar1,Ile8-Ang IIspecifically bound to AT1 receptor in rat hepatic membranes. These AT1 receptor binding studiesrevealed nanomolar affinity in several of the compounds under study. The most potent ligands4b,t were found to be equipotent with losartan and possessed either a 3-tetrazolylquinoline ora 2-amino-3-quinolinecarboxylic moiety, respectively. Moreover, some selected compounds wereevaluated for antagonism of Ang II-induced contraction in rabbit aortic strips, and the mostpotent compounds in the binding test 4b,t were slightly more potent than losartan in inhibitingAng II-induced contraction. Finally, the most relevant structure-affinity relationship data wererationalized by means of computational studies performed on the isolated ligands as well asby computational simulations on the ligands complexed with a theoretical AT1 receptor model.

2004 - Erratum: Structural features of the inactive and active states of the melanin-concentrating hormone receiptors: Insights from molecular simulations (Proteins: Structure, Function and Genetics (2004) 56 (430-448)) [Articolo su rivista]
Vitale, R. M.; Pedone, C.; De Benedetti, P. G.; Fanelli, F.
abstract

2004 - Structural features of the inactive and active states of the melanin-concentrating hormone receptors: Insights from molecular simulations [Articolo su rivista]
R. M., Vitale; C., Pedone; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

Comparative molecular dynamics simulations of both subtypes 1 and 2 of the melanin-concentrating hormone receptor (MCHR1 and MCHR2, respectively) in their free and hormone-bound forms have been carried out. The hormone has been used in its full-length and truncated forms, as well as in 16 mutated forms. Moreover, MCHR1 has been simulated in complex with T-226296, a novel orally active and selective antagonist. The comparative analysis of an extended number of receptor configurations suggests that the differences between inactive (i.e., free and antagonist-bound) and active (i.e., agonist-bound) states of MCHRs involve the receptor portions close to the E/DRY and NPxxY motifs, with prominence to the cytosolic extensions of helices 2, 3, 6, and 7. In fact, the active forms of these receptors share the release of selected intramolecular interactions found in the inactive forms, such as that between R3.50 of the E/DRY motif and D2.40, and that between Y7.53 of the NPxxY motif and F7.60. Another feature of the active forms of both MCHRs is the approach of helix 8 to the cytosolic extension of helix 3. These features of the active forms are concurrent with the opening of a cleft at the cytosolic end of the helix bundle. For both MCHRs, the agonist-induced chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor.

2004 - Synthesis, screening, and molecular modeling of new potent and selective antagonists at the alpha(1d) adrenergic receptor [Articolo su rivista]
A., Leonardi; D., Barlocco; F., Montesano; G., Cignarella; G., Motta; R., Testa; E., Poggesi; M., Seeber; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the aid adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially, held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three alpha(1)-AR subtypes and of the 5-HT1A receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the alpha(1d)-AR and the 5-HT1A receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BAN 7378 and 69 into the putative binding sites of the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR, and the 5-HT1A receptors suggest that the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4, 5, 6 and extracellular loop 2, (E2), whereas the spirocyclic ring of the ligand docks into a site formed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SAR data produced in this work. Furthermore, the binding site of the imide moiety does not allow for the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding, interactions, consistent with the SAR data, in particular with the results obtained with the lactam derivative 128. The results of docking simulations also suggest that the second and third extracellular loops may act as selectivity filters for the substituted phenylpiperazines. The most potent and selective compounds for alpha(1d) adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073), are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.

2003 - Adenosine A(2A)-dopamine D2 receptor-receptor heteromerization - Qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer [Articolo su rivista]
M., Canals; D., Marcellino; Fanelli, Francesca; F., Ciruela; DE BENEDETTI, Pier Giuseppe; Sr, Goldberg; K., Neve; K., Fuxe; Agnati, Luigi Francesco; As, Woods; S., Ferre; C., Lluis; M., Bouvier; R., Franco
abstract

There is evidence for strong functional antagonistic interactions between adenosine A2A receptors (A2ARs) and dopamine D2 receptors (D2Rs). Although a close physical interaction between both receptors has recently been shown using co-immunoprecipitation and co-localization assays, the existence of a A2AR-D2R protein-protein interaction still had to be demonstrated in intact living cells. In the present work, fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) techniques were used to confirm the occurrence of A2AR-D2R interactions in co-transfected cells. The degree of A2AR-D2R heteromerization, measured by BRET, did not vary after receptor activation with selective agonists, alone or in combination. BRET competition experiments were performed using a chimeric D2R-D1R in which helices 5 and 6, the third intracellular loop (I3), and the third extracellular loop (E3) of the D2R were replaced by those of the dopamine D1 receptor (D1R). Although the wild type D2R was able to decrease the BRET signal, the chimera failed to achieve any effect. This suggests that the helix 5-I3-helix 6-E3 portion of D2R holds the site(s) for interaction with A2AR. Modeling of A2AR and D2R using a modified rhodopsin template followed by molecular dynamics and docking simulations gave essentially two different possible modes of interaction between D2R and A2AR. In the most probable one, helix 5 and/or helix 6 and the N-terminal portion of I3 from D2R approached helix 4 and the C-terminal portion of the C-tail from the A2AR, respectively.

2003 - Development of an IL-6 antagonist peptide that induces apoptosis in IL-6 dependent 7TD1 cells. [Articolo su rivista]
Manfredini, Rossella; Tenedini, Elena; M., Siena; Tagliafico, Enrico; Montanari, Monica; Grande, Alexis; ZANOCCO MARANI, Tommaso; C., Poligani; Zini, Roberta; A., Bergamaschi; DE RIENZO, Francesca; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Ferrari, Sergio
abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the regulation of proliferation and differentiation of hematopoietic cells and in the pathogenesis of many diseases, including multiple myeloma. This study pursues a way to interfere with IL-6 pathway in an attempt to modulate its biological activity. Here we describe the rational design and biological evaluation of peptides able to antagonize the murine IL-6 activity by interfering with IL-6 Receptor alpha in 7TD1 cells, a IL-6-dependent B-cell line. Of the peptide tested, only Guess 4a is capable of interfering with IL-6 transducing pathway, therefore inducing growth arrest and apoptosis of 7TD1 cells.

2003 - Molecular dynamics simulations of the ligand-induced chemical information transfer in the 5-HT1A receptor [Articolo su rivista]
M., Seeber; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
abstract

Comparative molecular dynamics simulations of the 5-HT1A receptor in its empty as well as agonist(i.e. active) and antagonist-bound (i.e. nonactive) forms have been carried out. The agonists 5-HT and (R)-8-OH-DPAT as well as the antagonist WAY100635 have been employed. The results of this study strengthen the hypothesis that the receptor portions close to the E/DRY/W motif, with prominence to the cytosolic extensions of helices 3 and 6, are particularly susceptible to undergo structural modification in response to agonist binding. Despite the differences in the structural/dynamics behavior of the two agonists when docked into the 5-HT1A receptor, they both exert a destabilization of the intrahelical and interhelical interactions found in the empty and antagonist-bound receptor forms between the arginine of the E/DRY sequence and both D133(3.49) and E340(6.30). For both agonists, the chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 61 following the ligand interaction with selected amino acids in the extracellular half of the receptor, such as D 116(3.32), S199(5.42), Y195(5.38), and F361(6.51). A significant reduction in the bend at P360(6.50), as compared to the empty and the antagonist-bound receptor forms, is one of the features of the agonist-bound forms that is related to the breakage of the interhelical salt bridge between the E/DRY arginine and E340(6.30). Another structural feature, shared by the agonist-bound receptor forms and not by the empty and antagonist-bound forms, is the detachment of helices 2 and 4, as marked by the movement of W161(4.50) away from helix 2, toward the membrane space.

2003 - Seeking for binding determinants of the prion protein to human plasminogen [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; E., Langella; V., Barone
abstract

Plasminogen (Pg), a pro-protease implicated in neuronal excitotoxicity, has recently been identified as binding to prion protein (PrP) from several species. Although the precise effect of the binding of PrP to plasminogen in the course of prion-caused diseases has not yet been demonstrated, the implications of this important finding for diagnostic applications are straightforward. In this paper we have investigated the possible modes of interaction of PrP with plasminogen, by means of molecular modelling and computational simulation techniques. To this goal, we first exploited the information available for the mK2(Pg)/VEK-30 complex in order to identify the PrP residues which satisfy the specific electronic and geometric requirements needed to interact with the kringle lysine binding site, we compared the relevant mK2(Pg)/VEK-30 and mK2(Pg)/PrP interactions obtained from the simulated protein-protein complexes and we assessed the docking hypothesis utilized for the mK2(Pg)/PrP complex by simulating the interaction of PrP with the multi-kringle angiostatin, a more realistic model of the physiological target. The results obtained will be instrumental for planning experiments tailored to clarify the role of the plasminogen activator system in prion-related diseases and, eventually, for mimicking dominant binding determinants through structure-based drug design.

2003 - Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity [Articolo su rivista]
M., Anzini; L., Canullo; C., Braile; A., Cappelli; A., Gallelli; S., Vomero; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; M., Rizzo; S., Collina; O., Azzolina; M., Sbacchi; C., Ghelardini; N., Galeotti
abstract

The synthesis and biological evaluation of a series of new derivatives of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), are reported. Chemical and pharmacological studies on compounds 6 have been pursued with the aim of expanding the SAR data and validating the previously proposed model of interaction of this class of compounds with the kappa-opioid receptor. The synthesis of the previously described compounds 6 has been reinvestigated in order to obtain a more direct synthetic procedure. To study the relationship between the stereochemistry and the receptor binding affinity, compounds 6e and 6k were selected on the basis of their evident structural resemblance to tifluadom. Since a different specificity of action could be expected for the enantiomers of 6e and 6k, owing to the results shown by (S)- and (R)-tifluadom, their racemic mixtures have been resolved by means of liquid chromatography with chiral stationary phases (CSP), and the absolute configuration of the enantiomers has been studied by circular dichroism (CD) and H-1 NMR techniques. Moreover, some new 2-[(acylamino)ethyl]-1,4-benzodiazepine derivatives, 6a-d,f,g,j, have been synthesized, while the whole series (6a-o) has been tested for its potential affinity toward human cloned kappa-opioid receptor. The most impressive result obtained from the binding studies lies in the fact that this series of 2-[2-(acylamino)ethyll-1,4-benzodiazepine derivatives binds the human cloned kappa-opioid receptor subtype very tightly. Indeed, almost all the ligands within this class show subnanomolar K-i values, and the least potent compound 6o shows, in any case, an affinity in the nanomolar range. A comparison of the affinities obtained in human cloned kappa-receptor with the correspondent one obtained in native guinea pig kappa-receptor suggests that the human cloned kappa-receptor is less effective in discriminating the substitution pattern than the native guinea pig kappa-receptor. Furthermore, the results obtained are discussed with respect to the interaction with the homology model of the human kappa-opioid receptor, built on the recently solved crystal structure of rhodopsin. Finally, the potential antinociceptive and antiamnesic properties of compounds 6e and 6i have been investigated by means of the hot-plate and passive avoidance test in mice, respectively.

2002 - Erratum: "Novel potent 5-HT3 receptor ligands based on the pyrrolidone structure. Effects of the quaternization of the basic nitrogen on the interaction with 5-HT3 receptor" (Bioorganic and Medicinal Chemistry (2002) 10 (2681) PII: S0968089602000937) [Altro]
Cappelli, A.; Gallelli, A.; Braile, C.; Anzini, M.; Vomero, S.; Mennuni, L.; Makovec, F.; Menziani, Maria Cristina; De Benedetti, P. G.; Donati, A.; Giorgi, G.
abstract

Errata corrige

2002 - Novel 5-HT(3) receptor ligands based on the pyrrolidone structure: synthesis, biological evaluation, and computational rationalization of the ligand-receptor interaction modalities [Articolo su rivista]
A., Cappelli; M., Anzini; S., Vomero; L., Mennuni; F., Makovec; E., Doucet; M., Hamon; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; G., Giorgi; C., Ghelardini; S., Collina
abstract

Novel 5-HT(3) receptor ligands based on the pyrrolidone structure: synthesis, biological evaluation, and computational rationalization of the ligand-receptor interaction modalities

2002 - Novel potent 5-HT3 receptor ligands based on the pyrrolidone structure. Effects of the quaternization of the basic nitrogen on the interaction with 5-HT3 receptor [Articolo su rivista]
A., Cappelli; A., Gallelli; C., Braile; M., Anzini; S., Vomero; L., Mennuni; F., Makovec; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; A., Donati; G., Giorgi
abstract

The results of a comprehensive structure-affinity relationship study on the effect of the quaternization (i.e., N-methylation) of structurally different ligands in the classes of tropane and quinuclidine derivatives are described. This study shows that the effects of the quaternization of the basic nitrogen of these 5-HT3 receptor ligands appear to be strictly structure-dependent suggesting that different binding modes are operative at 5-HT3 receptor binding site. The different effect of the quaternization of the basic nitrogen of structurally different ligands were rationalized in tern-is of the interaction with the receptor by means of the combined use of experimental techniques (X-ray diffraction and NMR studies) and computational simulation studies. (C) 2002 Elsevier Science Ltd. All rights reserved.

2002 - The Interactions of 5-HT3 Receptor with Arylpiperazine, Tropane, and Quinuclidine Ligands [Articolo su rivista]
A., Cappelli; M., Anzini; S., Vomero; L., Mennuni; F., Makovec; M., Hamon; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina
abstract

The Interactions of 5-HT3 Receptor with Arylpiperazine, Tropane, and Quinuclidine Ligands

2001 - A computational model of the 5-HT3 receptor extracellular domain: search for ligand binding sites [Articolo su rivista]
Menziani, Maria Cristina; DE RIENZO, Francesca; A., Cappelli; M., Anzini; DE BENEDETTI, Pier Giuseppe
abstract

A three-dimensional model of the 5-HT3 receptor extracellular domain has been derived on the basis of the nicotinic acetylcholine receptor model recently published by Tsigelny et al. Maximum complementarity between the position and characteristics of mutated residues putatively involved in ligand interaction and the pharmacophoric elements derived by the indirect approach applied on several series of 5-HT3 ligands have been exploited to gain insights into the ligand binding modalities and to speculate on the mechanistic role of the structural components. The analysis of the three-dimensional model allows one to distinguish among amino acids that exert key roles in ligand interactions, subunit architecture, receptor assembly and receptor dynamics. For some of these, alternative roles with respect to the ones hypothesized by experimentalists are assigned. Different binding modalities for agonists and antagonists are highlighted, and residues which probably play a role in the transduction of binding into a change in conformational state of the receptor are suggested.

2001 - Electrostatic analysis and Brownian dynamics simulation of the association of plastocyanin and cytochrome F [Articolo su rivista]
DE RIENZO, Francesca; Rr, Gabdoulline; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Rc, Wade
abstract

The oxidation of cytochrome f by the soluble cupredoxin plastocyanin is a central reaction in the photosynthetic electron transfer chain of all oxygenic organisms. Here, two different computational approaches are used to gain new insights into the role of molecular recognition and protein-protein association processes in this redox reaction. First, a comparative analysis of the computed molecular electrostatic potentials of seven single and multiple point mutants of spinach plastocyanin (D42N, E43K, E43N, E43Q/D44N, E59K/E60Q, E59K/E60Q/E43N, Q88E) and the wt protein was carried out. The experimentally determined relative rates (k(2)) for the set of plastocyanin mutants are found to correlate well (r(2) = 0.90 - 0.97) with the computed measure of the similarity of the plastocyanin electrostatic potentials. Second, the effects on the plastocyanin/cytochrome f association rate of these mutations in the plastocyanin eastern site were evaluated by simulating the association of the wild type and mutant plastocyanins with cytochrome f by Brownian dynamics. Good agreement between the computed and experimental relative rates (k(2)) (r(2) = 0.89 - 0.92) was achieved for the plastocyanin mutants. The results obtained by applying both computational techniques provide support for the fundamental role of the acidic residues at the plastocyanin eastern site in the association with cytochrome f and in the overall electron-transfer process.

2001 - Mutational and computational analysis of the alpha-1b adrenergic receptor.Involvement of basic and hydrophobic residues in receptor activation and G protein coupling [Articolo su rivista]
P. J., Greasley; Fanelli, Francesca; A., Scheer; L., Abuin; M., NENNINGER TOSATO; DE BENEDETTI, Pier Giuseppe; S., Cotecchia
abstract

To investigate their role in receptor coupling to G(q), we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the alpha(1b)-adrenergic receptor (AR). The wild type and mutated receptors were expressed in COS-7 cells and characterized for their ligand binding properties and ability to increase inositol phosphate accumulation. The experimental results have been interpreted in the context of both an ab initio model of the alpha(1b)-AR and of a new homology model built on the recently solved crystal structure of rhodopsin. Among the twenty-three basic amino acids mutated only mutations of three, Arg(254) and Lys(258) in the third intracellular loop and Lys(291) at the cytosolic extension of helix 6, markedly impaired the receptor-mediated inositol phosphate production. Additionally, mutations of two conserved hydrophobic residues, Val(147) and Leu(151) in the second intracellular loop had significant effects on receptor function. The functional analysis of the receptor mutants in conjunction with the predictions of molecular modeling supports the hypothesis that Arg(254), Lys(258), as well as Leu(151) are directly involved in receptor-G protein interaction and/or receptor-mediated activation of the G protein. In contrast, the residues belonging to the cytosolic extensions of helices 3 and 6 play a predominant role in the activation process of the alpha(1b)-AR. These findings contribute to the delineation of the molecular determinants of the alpha(1b)-AR/G(q) interface.

2001 - Phenylpiperazinylalkylamino substituted pyridazinones as potent alpha(1) adrenoceptor antagonists [Articolo su rivista]
D., Barlocco; G., Cignarella; V., Dal Piaz; M. P., Giovannoni; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca; F., Montesano; E., Poggesi; A., Leonardi
abstract

QSAR models have been used for designing a series of compounds characterized by a N-phenylpiperazinylalkylamino moiety linked to substituted pyridazinones, which have been synthesized. Measurements of the binding affinities of the new compounds toward the alpha(1a)-, alpha(1b)-, and alpha(1d)-AR cloned subtypes as well as the 5-HT(1A) receptor have been done validating, at least in part, the estimations of the theoretical models. This study provides insight into the structure activity relationships of the alpha(1)-ARs ligands and their alpha(1)-AR/5-HT(1A) selectivity.

2001 - The 2-Methoxyethanol + 1,2-Dimethoxyethane + Water Ternary System: Static Relative Permittivity from -10 to 80 °C [Articolo su rivista]
Cocchi, Marina; DE BENEDETTI, Pier Giuseppe; Marchetti, Andrea; Menziani, Maria Cristina; Seeber, Renato; Tassi, Lorenzo; Ulrici, Alessandro
abstract

Static relative permittivities of the 2-methoxyethanol + 1,2-dimethoxyethane + water ternary solvent system were measured as a function of temperature (-10 less than or equal to t/degreesC less than or equal to 80) and of composition, over the whole molar fractions range 0 less than or equal to x(1), x(2), x(3) less than or equal to 1. The experimental values have been used to test some empirical relationships accounting for the dependence of epsilon on T. x(i), and on T, x(i) couples of values. A comparison between calculated and experimental data shows that these relationships can be profitably employed to predict E values in correspondence to experimental data gaps. The excess dielectric permittivity, epsilon (E), assumes, in the most cases, negative values for any compositions of the mixtures. while the values of the excess molar polarization, PE, are positive. The large values of the excess quantities are indicative of the strong specific interactions among similar, as well as different molecules in the mixtures. Discussion of the data in terms of Kirkwood correlation factor also gives information on the short-range intermolecular interactions among the components. suggesting the formation of two-components adducts rather than of than mure complex moieties involving all three molecular species.

2000 - Mutational analysis of the highly conserved arginine within the Glu/Asp-Arg-Tyr motif of the alpha(1b)-adrenergic receptor: effects on receptor isomerization and activation [Articolo su rivista]
Scheer, A.; Costa, T.; Fanelli, Francesca; MHAOUTY KODJA, S.; Abuin, L.; NENNIGER TOSATO, M.; Cotecchia, S.; DE BENEDETTI, Pier Giuseppe
abstract

We have suggested previously that both the negatively and positively charged residues of the highly conserved Glu/Asp-Arg-Tyr (E/DRY) motif play an important role in the activation process of the alpha(1b)-adreneric receptor (AR). In this study, R143 of the E/DRY sequence in the alpha(1b)-AR was mutated into several amino acids (Lys, His, Glu, Asp, Ala, Asn, and Ile). The charge-conserving mutation of R143 into lysine not only preserved the maximal agonist-induced response of the alpha(1b)-AR, but it also conferred high degree of constitutive activity to the receptor. Both basal and agonist-induced phosphorylation levels were significantly increased for the R143K mutant compared with those of the wild-type receptor. Other substitutions of R143 resulted in receptor mutants with either a small increase in constitutive activity (R143H and R143D), impairment (R143H, R143D), or complete loss of receptor-mediated response (R143E, R143A, R143N, R143I). The R413E mutant displayed a small, but significant increase in basal phosphorylation despite being severely impaired in receptor-mediated response. Interestingly, all the arginine mutants displayed increased affinity for agonist binding compared with the wild-type alpha(1b)-AR. A correlation was found between the extent of the affinity shift and the intrinsic activity of the agonists. The analysis of the receptor mutants using the allosteric ternary complex model in conjunction with the results of molecular dynamics simulations on the receptor models support the hypothesis that mutations of R143 can drive the isomerization of the alpha(1b)-AR into different states, highlighting the crucial role of this residue in the activation process of the receptor.

2000 - The ad hoc supermolecule approach to receptor ligand design [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina
abstract

Among the ligand design methods based on the theoretical QSAR paradigm, the simple ad hoc supermolecule approach is presented and applied to a highly non-congeneric set of a1-adrenergic receptor antagonists. The performance of the approach is satisfactory and highlights its (semi)quantitative ligand design potentiality.

2000 - The α1a and α1b-adrenergic receptor subtypes: molecular mechanisms of receptor activation and of drug action [Relazione in Atti di Convegno]
S., Cotecchia; O., Rossier; Fanelli, Francesca; A., Leonardi; DE BENEDETTI, Pier Giuseppe
abstract

In this chapter we summarize some aspects of the structure-functional relationship of the α 1a and α 1b-adrenergic receptor subtypes related to the receptor activation process as well as the effect of different alpha-blockers on the constitutive activity of the receptor. Molecular modeling of the α 1a and α 1b-adrenergic receptor subtypes and computational simulation of receptor dynamics were useful to interpret the experimental findings derived from site directed mutagenesis studies.

2000 - Theoretical investigation of substrate specificity for cytochromes p450 IA2, p450 IID6 and p450 IIIA4 [Articolo su rivista]
DE RIENZO, Francesca; Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural features and in their interaction properties with fifty specific and non-specific substrates. Substrate/enzyme complexes were obtained by means of both automated rigid and flexible body docking. The comparative analysis of the three cytochromes and the selected substrates, in their free and bound forms, allowed for the building of semi-quantitative models of substrate specificity based on both molecular and intermolecular interaction descriptors. The results of this study provide new insights into the molecular determinants of substrate specificity for the three different eukaryotic P450 isozymes and constitute a useful tool for predicting the specificity of new compounds.

1999 - Activation mechanism of human oxytocin receptor: A combined study of experimental and computer-simulated mutagenesis [Articolo su rivista]
Fanelli, Francesca; P., Barbier; D., Zanchetta; DE BENEDETTI, Pier Giuseppe; B., Chini
abstract

The aim of this study was to investigate the molecular changes associated with the transition of the human oxytocin receptor from its inactive to its active states. Mutation of the conserved arginine of the glutamate/aspartate-arginine-tyrosine motif located in the second intracellular domain gave rise to the first known constitutively active oxytocin receptor (R137A), whereas mutation of the aspartic acid located in the second transmembrane domain led to an inactive receptor (D85A). The structural features of the constitutively active and inactive receptor mutants were compared with those of the wild type in its free and agonist-bound states. The results suggest that, although differently triggered, the activation process induced by the agonist and the activating mutation are characterized by the opening of a solvent exposed site formed by the 2nd intracellular loop, the cytosolic extension of helix 5, and the 3rd intracellular loop; on the contrary, the D85A mutation prevents oxytocin from triggering the opening of a cytosolic site. On the basis of these findings, we hypothesize that this cytosolic crevice plays an important role in G protein recognition. Finally, comparative analysis of the free- and agonist-bound forms of the wild-type oxytocin receptor and alpha(1B) adrenergic receptor suggests that the highly conserved polar amino acids and the seven helices play similar mechanistic roles in the different G protein-coupled receptors.

1999 - Constitutively active receptor mutants as probes for studying the mechanisms underlying G protein-coupled receptor activation [Capitolo/Saggio]
S., Cotecchia; Fanelli, Francesca; A., Scheer; DE BENEDETTI, Pier Giuseppe
abstract

In this chapter, we illustrate a strategy to explore the potential molecular changes correlated with the transition from R to R* using the Gq-coupled alpha1B-AR as model system.

1999 - Development of Quantitative Structure-Property Relationships (QSPR) using calculated descriptors for the prediction of the physico-chemical properties (nD, r, bp, e and h) of a series of organic solvents. [Articolo su rivista]
Cocchi, Marina; DE BENEDETTI, Pier Giuseppe; Seeber, Renato; Tassi, Lorenzo; Ulrici, Alessandro
abstract

Quantitative structure-property relationship (QSPR) models were derived for predicting boiling point (at 760 mmHg), density (at 25 °C), viscosity (at 25 °C), static dielectric constant (at 25 °C), and refractive index (at 20 °C) of a series of pure organic solvents of structural formula X-CH2CH2-Y. A very large number of calculated molecular descriptors were derived by quantum chemical methods, molecular topology, and molecular geometry by using the CODESSA software package. A comparative analysis of the multiple linear regression techniques (heuristic and best multilinear regression) implemented in CODESSA, with the multivariate PLS/GOLPE method, has been carried out. The performance of the different regression models has been evaluated by the standard deviation of prediction errors, calculated for the compounds of both the training set (internal validation) and the test set (external validation). Satisfactory QSPR models, from both predictive and interpretative point of views, have been obtained for all the studied properties.

1999 - Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3 receptors [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Canullo, L; Mennuni, L; Makovec, F; Doucet, E; Hamon, M; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Bruni, G; Romeo, Mr; Giorgi, G; Donati, A.
abstract

Novel 5-HT3 receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT3 receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [H-3]granisetron from rat cortical membranes. These 5-HT3 receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT3 ligands related to quipazine with their receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT3 receptor-dependent [C-14]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT3 full agonist properties of compounds 7a and 8h,i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c,d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.

1999 - Relevance of theoretical molecular descriptors in quantitative structure-activity relationship analysis of alpha 1-adrenergic receptor antagonists [Articolo su rivista]
Menziani, Maria Cristina; Montorsi, Monia; DE BENEDETTI, Pier Giuseppe; Karelson, M.
abstract

A quantitative structure-activity relationship (QSAR) study of a wide series of structurally diverse alpha(1)-adrenergic receptor antagonists was performed using the CODESSA (Comprehensive Descriptors for Structural and Statistical Analysis) technique. Theoretical descriptors derived on a single structure and ad hoc defined size and shape descriptors were considered in the attempt of describing information relevant to receptor interaction. The relative effectiveness of these two classes of parameters in developing QSAR models for native (alpha(1A) and alpha(1B)) and cloned (alpha(1a), alpha(1b), and alpha(1d)) adrenergic receptor binding affinity, functional activity of vascular and lower urinary tract tissues, and in vitro and in vivo selectivity was evaluated. (C) 1999 Elsevier Science Ltd. All rights reserved.

1999 - Structure-function relationships of the alpha(1b)-adrenergic receptor [Articolo su rivista]
A., Scheer; Fanelli, Francesca; D., Diviani; DE BENEDETTI, Pier Giuseppe; S., Cotecchia
abstract

The alpha1b-adrenergic receptor (AR) is a member of the large superfamily of seven transmembrane domain (TMD) G protein-coupled receptors (GPCR). Combining site-directed mutagenesis of the alpha1b-AR with computational simulations of receptor dynamics, we have explored the conformational changes underlying the process of receptor activation, i.e. the transition between the inactive and active states. Our findings suggest that the structural constraint stabilizing the alpha1b-AR in the inactive form is a network of H-bonding interactions amongst conserved residues forming a polar pocket and R143 of the DRY sequence at the end of TMDIII. We have recently reported that point mutations of D142, of the DRY sequence and of A293 in the distal portion of the third intracellular loop resulted in ligand-independent (constitutive) activation of the alpha1b-AR. These constitutively activating mutations could induce perturbations resulting in the shift of R143 out of the polar pocket. The main role of R143 may be to mediate receptor activation by triggering the exposure of several basic amino acids of the intracellular loops towards the G protein. Our investigation has been extended also to the biochemical events involved in the desensitization process of alpha1b-AR. Our results indicate that immediately following agonist-induced activation, the alpha1b-AR can undergo rapid agonist-induced phosphorylation and desensitization. Different members of the G protein coupled receptor kinase family can play a role in agonist-induced regulation of the alpha1b-AR. In addition, constitutively active alpha1b-AR mutants display different phosphorylation and internalization features. The future goal is to further elucidate the molecular mechanism underlying the complex equilibrium between activation and inactivation of the alpha1b-AR and its regulation by pharmacological substances. These findings can help to elucidate the mechanism of action of various agents displaying properties of agonists or inverse agonists at the adrenergic system.

1999 - Synthesis, pharmacological evaluation, and structure-activity relationship and quantitative structure-activity relationship studies on novel derivatives of 2,4-diamino-6,7-dimethoxyquinazoline alpha(1)-adrenoceptor antagonists [Articolo su rivista]
Leonardi, A; Motta, G; Boi, C; Testa, R; Poggesi, E; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina
abstract

A new series of novel piperazine and non-piperazine derivatives of 2,4-diamino-6,7-dimethoxyquinazoline was synthesized and evaluated for binding affinity toward alpha(1)-adrenergic and other G-protein-coupled aminergic receptors. The alpha(1)-adrenoceptor (AR) subtype selectivity was also investigated for the most interesting compounds. Only compound 16 showed moderate selectivity toward the alpha(1b)-AR subtype. Selected compounds were tested in vivo in a dog model indicating activity on blood pressure and on the lower urinary tract. Compound 10 showed in vivo potency close to that of prazosin. Powerful interpretative and predictive theoretical QSAR models have been obtained. The theoretical descriptors employed in the rationalization of the alpha(1)-adrenergic binding affinity depict the key features for receptor binding which can be summarized in an electrostatic interaction between the protonated amine function and a primary nucleophilic site of the receptor, complemented by short-range attractive (polar and dispersive) and repulsive (steric) intermolecular interactions. Moreover, on predictive grounds, the ad hoc derived size and shape QSAR model developed in a previous paper (Rastelli, G.; et al. J. Mol. Struct. 1991, 251, 307-318) proved to be successful in predicting nanomolar alpha(1)-adrenergic binding affinity for compound 28.

1999 - Theoretical study on receptor-G protein recognition: new insights into the mechanism of the α1b-adrenergic receptor activation [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Scheer; S., Cotecchia; DE BENEDETTI, Pier Giuseppe
abstract

Theoretical study on receptor/G protein recognition: new insights into the mechanism of the α1b-adrenergic receptor activation.

1999 - Theoretical study on the electrostatically driven step of receptor-G protein recognition [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Scheer; Cotecchia, S.; DE BENEDETTI, Pier Giuseppe
abstract

Theoretical study on the electrostatically driven step of receptor-G protein recognition

1998 - Ab initio modeling and molecular dynamics simulation of the alpha 1b-adrenergic receptor activation [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Scheer; S., Cotecchia; DE BENEDETTI, Pier Giuseppe
abstract

This work describes the ab initio procedure employed to build an activation model for the alpha(1b)-adrenergic receptor (alpha(1b)-AR). The first version of the model was progressively modified and complicated by means of a many-step iterative procedure characterized by the employment of experimental validations of the model in each upgrading step. a combined simulated (molecular dynamics) and experimental mutagenesis approach was used to determine the structural and dynamic features characterizing the inactive and active states of alpha(1b)-AR. The latest version of the model has been successfully challenged with respect to its ability to interpret and predict the functional properties of a large number of mutants. The iterative approach employed to describe alpha(1b)-AR activation in terms of molecular structure and dynamics allows further complications of the model to allow prediction and interpretation of an ever-increasing number of experimental data.

1998 - Computer modeling of size and shape descriptors of alpha 1-adrenergic receptor antagonists and quantitative structure-affinity/selectivity relationships [Articolo su rivista]
Montorsi, Monia; Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Computational chemistry and molecular modeling procedures allow us to define and compute ad hoc size and shape descriptors on the different prototropic forms assumed by drugs in biotest solutions. Together with experimental data measured on a well-identified target receptor, these descriptors are essential elements for obtaining simple, consistent, comparable, and easily interpretable theoretical quantitative structure-activity relationship (QSAR) models based on the ligand similarity-target receptor complementarity paradigm. In this context, quantitative size and shape affinity/subtype selectivity relationships have been modeled for a large set of very heterogeneous alpha(1a)-, alpha(1b)-, and alpha(1d)-adrenergic receptor antagonists. The linear QSAR models generated have been validated by predicting both binding affinity and selectivity of a test set of noncongeneric antagonists. The satisfactory results obtained highlight both the simplicity and the versatility of the approach presented.

1998 - Molecular mechanisms involved in the activation and regulation of the alpha 1-adrenergic receptor subtypes [Articolo su rivista]
S., Cotecchia; A., Scheer; D., Diviani; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

The adrenergic receptors (ARs) belong to the superfamily of membrane-bound G protein coupled receptors (GPCRs). Our investigation has focused on the structure-function relationship of the alpha 1b-AR subtype used as the model system for other GPCRs. Site-directed mutagenesis studies have elucidated the structural domains of the alpha 1b-AR involved in ligand binding, G protein coupling or desensitization. In addition, a combined approach using site-directed mutagenesis and molecular dynamics analysis of the alpha 1b-AR has provided information about the potential mechanisms underlying the activation process of the receptor, i.e. its transition from the 'inactive' to the 'active' conformation.

1998 - Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Mennuni, L; Makovec, F; Doucet, E; Hamon, M; Bruni, G; Romeo, Mr; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Langer, T.
abstract

Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a K-i value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [C-14]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximate to 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.

1998 - Theoretical descriptors in quantitative structure - Affinity and selectivity relationship study of potent N4-substituted arylpiperazine 5-HT1(Alpha) receptor antagonists [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Karelson, M.
abstract

The ability of ad hoc defined size and shape descriptors and theoretical descriptors derived on a single structure to give poweful interpretative and predictive QSAR models has been compared and evaluated with respect to the quality of the pharmacological data available for a series of structurally diverse 5-HT1(A) receptor antagonists, displaying selectivity towards the alpha 1-adrenergic receptor. (C) 1998 Elsevier Science Ltd. All rights reserved.

1998 - Use of the supermolecule approach to derive molecular similarity descriptors for QSAR analysis. [Articolo su rivista]
Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

A relevant aspect in quantitative structure-activity (QSAR) and structure-selectivity (QSSR) relationships studies is the choice of the most appropriate molecular descriptors both with respect to the molecular series considered and the known or hypothetical mechanism of drug action. We have recently shown that ad hoc derived size and shape descriptors have been successful to derive QSAR and QSSR models for #a 1-adrenergic antagonists, 5-HT1A serotoninergic receptor ligands and M 1 muscarinic ligands, especially when dealing with non congeneric series of molecules. These de- scriptors describe the size-shape similarity with respect to a reference supermolecule which is obtained by superposition of the most active(selective) and structural different compounds, better if rigids. Molecular similarity indices based on molecular electrostatic potential (MEP) have found, as well, widespread use in the QSAR area. In the present study we extend the use of the supermolecule as a reference structure also in the context of MEP similarity. We have defined an ad hoc MEP similarity index with respect to the supermolecule using the same formalism of Hodgkin and Richards. The MEP of the supermolecule is computed as the average MEP of the compounds defining the supermolecule. A FORTRAN code is implemented to optimize the superposition of the ligands on the reference super- molecule in order to maximize the values of the ad hoc similarity descriptors defined in this study. The performance of the different matching criteria and the different ad hoc molecular similarity indices derived with the supermolecule approach are tested in QSAR modeling of the binding affinity and efficacy of a wide ranging series of M 1 muscarinic ligands previously studied.

1997 - Alpha 1-adrenoceptor subtype selectivity: Molecular modelling and theoretical quantitative structure-affinity relationships [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; R., Testa; A., Leonardi
abstract

This study constitutes a preliminary rationalization, at the molecular level, of antagonist selectivity towards the three cloned alpha 1-adrenergic receptor (alpha 1-AR) subtypes. Molecular dynamics simulations allowed a structural/dynamics analysis of the seven alpha-helix-bundle models of the bovine alpha 1a-, hamster alpha 1b-, and rat alpha 1d-AR subtypes. The results showed that the transmembrane domains of these subtypes have different dynamic behaviours and different topographies of the binding sites, which are mainly constituted by conserved residues. In particular, the alpha 1a-AR binding site is more flexible and topographically different with respect to the other two subtypes. The results of the theoretical structural/dynamics analysis of the isolated receptors are consistent with the binding affinities of the 16 antagonists tested towards the three cloned alpha 1-AR subtypes. Moreover, the theoretical quantitative structure-affinity relationships obtained from the antagonist-receptor interaction models further corroborates the hypothesis that selectivity towards one preferential subtype is mainly modulated by receptor and/or ligand distortion energies. In other words, subtype selectivity seems to be mainly guided by the dynamic complementarity (induced fit) between ligand and receptor. On the basis of the quantitative models presented it is possible to predict both affinities and selectivities of putative alpha 1-AR ligands as well as to estimate the theoretical alpha 1-AR subtype affinities and selectivities of existing antagonists.

1997 - Conformational analysis and theoretical quantitative size and shape-affinity relationships of N-4-protonated N-1-arylpiperazine 5-HT1A serotoninergic ligands [Articolo su rivista]
Cocchi, Marina; Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Conformational analysis for 24 arylpiperazines in their neutral and N-4-protonated forms has been performed in the AM1 framework. Both these derivatives and eight reference compounds considered in this study are ligands of the 5-HT1A serotoninergic receptor. Quantum chemical reactivity indices, solvation free energies (AMSOL 5.0) and molecular modelling derived ad hoc size and shape descriptors have been computed and correlated with the literature 5-HT1A binding affinity data values. The quantitative size-shape affinity relationships obtained confirm the validity and versatility of the ad hoc descriptors employed. A different role has been postulated for the neutral and protonated forms of the arylpiperazines considered in the molecular recognition process of the 5-HT1A receptor binding site.

1997 - Constitutively active α1B-adrenergic receptor mutants: potential mechanisms underlying receptor activation [Relazione in Atti di Convegno]
A., Scheer; Fanelli, Francesca; T., Costa; DE BENEDETTI, Pier Giuseppe; S., Cotecchia
abstract

Not Available

1997 - Molecular dynamics of guest radicals in urea inclusion compounds [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Segre, Ulderico; Brustolon, M.
abstract

Molecular dynamics simulations of several radical guests included in urea clathrates have been performed for a period of 1 ns. The starting conformations of the radicals have been obtained by AM1 quantum mechanical computations. The host matrix has been modelled as a single channel formed by 47 or 72 urea molecules, and different constraints imposed on the urea molecule positions have been tested to optimize the effect of the host confinement on the guest radicals. Two kinds of motion have been considered, the internal dynamics of the methylene group beta to the radical centre and the rotation of the guest inside the host channel. The simulation results have been compared with experimental data obtained by electron paramagnetic resonance spectroscopy. Good agreement is found for the internal motion when a finite harmonic constraint is imposed on the urea carbonyl. The correlation time for the molecular rotation is estimated to be longer than the simulation period. The slow reorientation process should be controlled by the concurrent rearrangement of the host matrix.

1997 - Theoretical investigation of IL-6 multiprotein receptor assembly [Articolo su rivista]
Menziani, Maria Cristina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates cell growth, differentiation, and cellular functions in many cell lineages, Recently, evidences for the formation of an active hexameric complex with an IL-6:IL-6R alpha:gp130 stoichiometry of 2:2:2 have been obtained by different experimental approaches, Analysis of the electrostatic potential complementarity between IL-6 and its receptors has been used, in this study to guide the assembly of homology-based 3D models of the components, The results strongly support a mechanism whereby the active cytokine (IL-6: IL-6R alpha) associates with the signal transducing gp130 protein, and the trimeric complex formed further dimerizes to form the hexameric species. Furthermore, computational simulations of the multiprotein complexes provide a rationalization of data from mutation experiments and highlight some key protein-protein interactions which have not yet been the subject of mutagenesis studies.

1996 - Computational simulations of stem-cell factor c-Kit receptor interaction [Articolo su rivista]
Menziani, Maria Cristina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Stem-cell factor (SCF) is a noncovalent homodimeric cytokine that exhibits profound biological function in the early stages of hematopoiesis by binding to a cell surface tyrosine kinase receptor that is encoded by the c-Kit proto-oncogene. The results obtained from a combined implementation of homology-based molecular modeling and computational simulations in the study of species-specific SCF/c-Kit interactions are reported. The structural models of the human and rat SCF Ligands are based on the close structural similarity to the cytokine M-CSF, whose C alpha structure has recently become available. The constant domains of the human Fc fragment are used as a template for the ligand binding domains of the c-Kit receptor. The factors responsible for the stabilization of the SCF quaternary structure and the molecular determinants for ligand recognition and ligand specificity have been identified by assessing the conformational, topographical, and dynamic features of the isolated ligands and of the ligand-receptor complexes.

1996 - Molecular structure and dynamics of some potent 5-HT3 receptor antagonists. Insight into the interaction with the receptor [Articolo su rivista]
Cappelli, A; Donati, A; Anzini, M; Vomero, S; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Langer, T.
abstract

The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally related to quipazine have been investigated by NMR spectroscopy and by computational methods in order to gain insight into the structure-activity relationships at a molecular level. The role of the different dynamic behaviour of these compounds in the binding to 5-HT3 receptors is discussed. A model of ligand-receptor interaction has been developed on the basis of molecular orbital calculations and on the reference ligands quipazine, ondansetron and LY278584. The interaction model proposed herein rationalizes the observed agonist-antagonist shift between quipazine and investigated compounds with the assumption of different but overlapping binding domains for antagonists and agonists at the 5-HT3 receptor. Copyright

1996 - Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Sbacchi, M; Clarke, Gd; Mennuni, L.
abstract

The synthesis and biological evaluation of a series of 2-substitued 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these studies were [I-125(BH)-CCK-8 in rat pancreas (CCK-A), [H-3]-(MeNLE(28,31))-CCK-8 in guinea pig cerebral cortex (CCK-B), and [H-3]U-69593 (kappa(1)), [H-3]DAMGO (mu), and [H-3]DADLE (delta) in guinea pig brain. All the title compounds were devoid of significant affinity for both CCK-A and CCK-B receptors, while some of them bound with nanomolar affinity and high selectivity for kappa-opioid receptors. In particular, the 2-thienyl derivative 7a (X = H) with a K-i = 0.50 nM represents a clear improvement with respect to tifluadom, showing a comparable potency but higher selectivity. The application of computational simulations and linear regression analysis techniques to the complexes between guinea pig kappa (kappa(1))-receptor and the title compounds allowed the identification of the structural determinants for recognition and quantitative elucidation of the structure-affinity relationships in this class of receptors.

1996 - The Heuristic-Direct approach to Quantitative Structure-Activity Relationship Analysis of Ligand-G Protein Coupled Receptor Complexes [Capitolo/Saggio]
Menziani, Maria Cristina; Fanelli, Francesca; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

The Heuristic-Direct approach to Quantitative Structure-Activity Relationship Analysis of Ligand-G Protein Coupled Receptor Complexes

1995 - Comparative molecular dynamics study of the seven-helix bundle arrangement of G-protein coupled receptors [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

A comparative molecular dynamics study has been performed on the seven-helix bundle arrangement of seven G-protein coupled receptors (GPCRs). They are hamster alpha(1B)-, human alpha(2)-, beta(2)-adrenergic, human D-2-dopaminergic, human 5-HT1A-serotoninergic, human ml-muscarinic receptors and bovine rhodopsin. Starting from a rhodopsin-like input structure and a bacteriorhodopsin-like input structure, a similar arrangement of the averaged helix bundles was obtained. This may be due to the topography of some fundamental polar positions in both the input structures which is substantially the same and dictates, through the establishment of similar H-bonding networks, the helix-helix packing. By comparing the averaged structures and the packing interaction parameters obtained for the GPCRs considered with that of bacteriorhodopsin, we observe that the GPCRs share a similar packing arrangement of their transmembrane helix bundles which differs from that of bacteriorhodopsin. The results obtained from the quantitative and comparative molecular modelling of the GPCRs constitute an important preliminary step in a general understanding of both structure-function and structure activity-selectivity relationships in these proteins, at the molecular level.

1995 - Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular dynamics simulations of the hamster alpha(1B)-adrenergic and the rat m3-muscarinic seven-helix bundle receptor models have been carried out. The free, agonist-bound and antagonist-bound forms have been considered, Moreover, three mutant forms of the m3-muscarinic receptor (N507-->A, N507-->D and N507-->S) have also been simulated; among these, the N507-->S mutant shows a constitutive activity, A comparative structural/dynamics analysis has been performed to elucidate (i) the perturbations induced by the functionally different ligands upon binding to their target receptor, (ii) the features of the three single-point mutants with respect to the receptor wild type and (iii) the properties shared by the agonist-bound forms of the alpha(1B)-adrenergic receptor and the m3-muscarinic receptor and by the constitutively active mutant N507-->S. The consistency obtained between the structural rearrangement of the transmembrane seven-helix bundle models considered, and the experimental pharmacological efficacies of the ligands and of the mutants, constitute an important validation of the 3-D models obtained and allow the inference of the mechanism of ligand- or mutation-induced receptor activation at the molecular level.

1995 - Molecular dynamics simulations of m3-muscarinic receptor activation and QSAR analysis [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular dynamics simulations of the rat m3-muscarinic seven-helix-bundle receptor models were performed on the free, agonist-bound and antagonist-bound forms. A comparative structural/dynamics analysis was performed in order to explain the perturbations induced by the functionally different ligands when binding to their target receptor. Theoretical quantitative structure-activity relationship models were developed; a good correlation was obtained between the interaction energies of the minimized average ligand-receptor complexes and the pharmacological affinities of the considered ligands. The consistency obtained between the structural rearrangement of the transmembrane seven-helix-bundle models considered and the experimental pharmacological efficacies and affinities of the ligands constitutes an important validation of the 3-D models proposed and allows the inference of the mechanism of ligand-induced or mutation-induced receptor activation at the molecular level.

1995 - Prototropic molecular forms and theoretical descriptors in QSAR analysis [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca
abstract

Computational chemistry allows us to define and compute ad hoc theoretical reactivity and size-shape descriptors on the different prototropic forms assumed by drugs in pharmacological test solutions. These are essential elements for obtaining simple, consistent, comparable and easily interpretable theoretical QSAR models based on the ligand similarity-target complementarity paradigm. In this context, theoretical QSAR models have been obtained for 34 structurally and pharmacologically (antagonists, partial agonists and full agonists) heterogeneous M(1)-muscarinic ligands and the above concepts have been highlighted.

1995 - Quantitative structure-affinity/selectivity relationship analysis on three-dimensional models of the complexes between the ETA and ETB receptors and C-terminal endothelin hexapeptide antagonists [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

The application of molecular modelling and regression analysis techniques to the complexes between the ET(A) and ET(B) receptors and a series of C-terminal endothelin hexapeptide antagonists allowed the identification of the structural determinants for recognition and the quantitative elucidation of the receptor structure-affinity/selectivity relationships.

1995 - The Heuristic-Direct Approach to QSAR Analysis of Ligand-G-Protein Coupled Receptor Complexes [Capitolo/Saggio]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Fanelli, Francesca; Cocchi, Marina
abstract

Not available

1995 - Theoretical QSAR analysis on three dimensional models of the complexes between peptide and non-peptide antagonists with the ETA and ETB receptors [Capitolo/Saggio]
Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Not available

1995 - Theoretical quantitative structure-activity relationship analysis of congeneric and non-congeneric α1-adrenoceptor antagonists: a chemometric study [Articolo su rivista]
Cocchi, Marina; Menziani, Maria Cristina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Molecular orbital calculations (AM1) and molecular modelling procedures (QUANTA/CHARMm) have been performed both on a congeneric (prazosin analogs) and on a non-congeneric series of alpha(1)-adrenergic antagonists. A large variety of theoretical molecular descriptors has been obtained and compared by principal component analysis (PCA). The generating optimal least squares estimations (GOLPE) procedure has been used to derive quantitative structure-activity relationships (QSARs). Good predictive QSAR models with a restricted pool of informative theoretical descriptors have been obtained. These results support the generality of the theoretical QSAR approach proposed; in fact both congeneric and non-congeneric molecular series were satisfactorily modeled. Moreover, the high and well-defined physical information content encoded in the theoretical descriptors considered allows the rationalization of the structural heterogeneity of the molecules examined as differences in the complementary intermolecular interactions of the studied ligands towards their common receptor.

1994 - The heuristic-direct approach to theoretical quantitative structure activity relationship analysis of α1- adrenoceptor ligands [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; A., Leonardi; DE BENEDETTI, Pier Giuseppe
abstract

The heuristic-direct quantitative structure-activity relationship approach has been applied to fifteen non-congeneric alpha1-adrenergic receptor (alpha1-AR) ligands interacting with the rat alpha1A/D-AR subtype. The good linear correlations, which have been obtained between calculated binding energies and the pharmacological affinities, allow one to predict the pharmacological affinity of new ligands. Moreover, according to the alpha1A/D-receptor model proposed, it has been possible to speculate on the amino acid residues which are mainly involved in the interaction with the ligands. This novel procedure consitutes a powerful tool for the design of new selective leads based on explicit intermolecular interactions and for suggesting site-directed mutagenesis studies, in order to give, iteractively, further support and improvement to the predictive and interpretative aspects of the model.

1994 - Theoretical quantitative size and shape activity and selectivity analyses of 5-HT1A serotonin and α1-adrenergic receptor ligands [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Cocchi, Marina; Menziani, Maria Cristina; Fanelli, Francesca
abstract

Quantum chemical reactivity indices and molecular modelling derived size and shape descriptors have been computed for 18 5-HT1A serotonin and alpha1-adrenergic receptor ligands. The quantitative size shape affinity selectivity relationships obtained support the general validity and versatility of the ad hoc size shape descriptors employed.

1993 - A MOLECULAR-DYNAMICS SIMULATION OF SEQUENCE-DIRECTED RECOGNITION PEPTIDES INTERACTING WITH BIGENDOTHELIN [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

Detailed insights into the mechanisms and forces responsible for the highly selective binding of three sequence-directed recognition peptides to bigendothelin are provided by the combined use of computer-aided model building techniques, molecular dynamics simulations and quantitative structure-activity analysis. The relevance of the analysis of the interactions between the peptides during the molecular dynamics simulation to peptide design is highlighted.

1993 - The heuristic-direct approach to quantitative structure-activity relationship analysis [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Fanelli, Francesca; Cocchi, Marina
abstract

The heuristic-direct approach to quantitative structure-activity relationship analysis

1993 - Theoretical quantitative structure-activity analysis and pharmacophore modelling of selective non congeneric α1a-adrenergic antagonists [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Cocchi, Marina; Menziani, Maria Cristina; Fanelli, Francesca
abstract

Quantitative structure-activity relationship (QSAR) analysis has been done by making use of theoretical molecular descriptors on 13 non-congeneric alpha1a-adrenoceptor antagonists. Linear QSAR models have been obtained between ad hoc molecular shape and size descriptors, defined with respect to a reference ''super-molecule'', and the antagonistic potency. These results, obtained for a highly non-congeneric set of molecules, increase the potential of this approach and the probability of designing new leads. Finally, the reference supermolecule represents the best three-dimensional complementarity towards the alpha1a-adrenoceptor subtype being modelled by superimposing the two most active and selective alpha1a-antagonists.

1993 - Theoretical quantitative structure-activity analysis of quinuclidine-based muscarinic cholinergic receptor ligands [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; Carotti, A; DE BENEDETTI, Pier Giuseppe
abstract

Quantitative structure-activity relationship analysis using ad hoc theoretical molecular descriptors was performed on a set of 22 quinuclidine-based muscarinic cholinergic receptor ligands. The results obtained support quantitatively a pharmacophoric interacting model which suggests that once the essential H-bonding interaction between the protonated quinuclidine nitrogen atom and a protophilic counterpart in the receptor is satisfied, different mechanisms of interaction become operative in order to differentiate between agonists, partial agonists and antagonists. In fact, the agonist behaviour is characterized by two H-bonding interactions, whereas mainly lipophilic interactions characterize the antagonistic behaviour. Finally, both the H-bond acceptor propensity of the agonists and lipophilic features of the antagonists are better accounted for by theoretical descriptors computed on the pharmacologically active protonated forms than by those computed on the neutral forms.

1993 - Three dimensional molecular modeling of the α1a-adrenoceptor. Direct 3D-QSAR modeling of selective antagonists [Capitolo/Saggio]
Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

three dimensional molecular modeling of the α1a-adrenoceptor. Direct 3D-QSAR modeling of selective antagonists

1992 - CORRELATION AND MULTIVARIATE ANALYSES OF SPECTROSCOPIC AND DIHYDROPTEROATE SYNTHASE INHIBITORY ACTIVITY DATA IN 4-AMINOARYL (MULTISUBSTITUTED ARYL) SULFONES [Articolo su rivista]
Cocchi, Marina; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Nuclear magnetic resonance (H-1 and C-13), vibrational spectroscopy, and quantum chemical calculations (complete neglect of differential overlap/2 [CNDO/2]) have been used to investigate 20 biologically active title compounds, inhibitors of the dihydropteroate synthase. The data obtained have been comparatively analyzed by correlation and multivariate analyses. The results obtained show that also in the case of multisubstitution the electronic effect can be rationalized in terms of electronic charge perturbations which are transmitted from the multisubstituted aryl ring to the common biofunctional moiety 4-NH2-C6H4-SO2- trough the SO2 group, mainly via hyperconjugation. Good predictions of both spectroscopic and biological data are obtained by the partial least squares method using quantum chemical descriptors.

1992 - ELECTRONIC AND ELECTROSTATIC ASPECTS OF CARBONIC-ANHYDRASE INHIBITION BY SULFONAMIDES [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

A theoretical conformational analysis was performed within the AM1 framework for three benzenesulphonamide carbonic anhydrase inhibitors in their neutral and anionic forms. The theoretical reactivity and electrostatic indices obtained are compared with both the enzymic inhibitory potencies and the molecular orbital indices computed using a simple theoretical model of the carbonic anhydrase-sulphonamide complex. Finally, the inhibitory activities of the sulphonamides considered were correlated with the proton exchange and charge transfer propensities of the inhibitors. The role of the zinc ion in the inhibition mechanism seems to be mainly connected with the generation of an electrostatic field which favours the correct orientation of the SO2NH2 group and its anticipated deprotonation.

1992 - Molecular mechanics and quantum chemical qsar analysis in carbonic anhydrase-heterocyclic sulfonamide interactions [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

The simulation of the interaction of carbonic anhydrase with 2-substituted 1,3,4-thiadiazole-5-sulfonamide derivatives has been carried out using molecular mechanics methods. The variation in inhibitory potency is very well accounted for by the calculated binding energies. In addition, certain theoretical molecular descriptors have proven to be suitable for modelling the interaction energy with specific residues in an extended environment of the active site metal Zn2+.

1992 - Molecular modeling and quantitaive structure activity relationship analysis using theoretical descriptors of 1,4-benzodioxan (WB-4101) related-compounds alpha-1-adrenergic antagonists [Articolo su rivista]
P., Venturelli; Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Quantitative structure-activity relationship analysis using theoretical molecular descriptors was done on a set of 30 1,4-benzodioxan (WB-4101) related compounds which are alpha1-adrenoceptor antagonists. The results obtained confirm quantitatively and in terms of reactivity and molecular shape descriptors, the results of previous qualitative structure-activity relationship studies. It was found that the protonated amine function plays a crucial role in the potency of the alpha1-adrenoceptor antagonism due to a charge reinforced hydrogen bond with a primary nucleophilic site of the receptor. Furthermore, the more electrophilic (high SN1LUMO values) the NH2+ group, the stronger the charge reinforced hydrogen bond with the receptor and the higher the blocking activity. It was also found that the three-dimensional shape of the antagonists is more similar to the shape of the most active reference molecule (WB-4101) the more potent antagonists are. Finally, the reactivity (E(LUMO)) and the ad hoc shape (V(D)(norm)) descriptors were used to obtain a bilinear equation which accounts for about 77% of the total variance in the pharmacological data.

1992 - THEORETICAL VERSUS EMPIRICAL MOLECULAR DESCRIPTORS IN MONOSUBSTITUTED BENZENES - A CHEMOMETRIC STUDY [Articolo su rivista]
Cocchi, Marina; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Cruciani, G.
abstract

Quantum chemical methods and molecular modeling techniques allow the definition of a large number of molecular and local quantities characterizing the reactivity, the shape and the binding properties of a molecule as well as of molecular fragments and substituents. This study is focused on a systematic comparison of the theoretical molecular descriptors with both empirical (Hammett's and Taft's substituent constants, hydrophobic parameter, Verloop's steric parameters etc.) and experimental (substituent induced chemical shifts, molecular weight and molecular refractivity) descriptors. Fifty selected monosubstituted benzenes, including some charged substituents have been computed in the AM1 framework. Several theoretical descriptors have been extracted from the AM1 electronic wavefunction as well as molecular modeling techniques and they have been analyzed by principal component analysis and the partial least squares method. The results obtained are consistent with previous principal component studies concerning empirical descriptors, and highlight the interdependencies among theoretical and empirical molecular descriptors.

1991 - A THEORETICAL-STUDY OF THE STRUCTURE OF BIG ENDOTHELIN [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe; Gilbert, Rg; Richards, Wg; Zamai, M; Caiolfa, Vr
abstract

Protein structure prediction and molecular dynamics simulations have been applied for elaborating the three dimensional structure of Big Endothelin (bigET). BigET is 38-amino acid peptide which is converted, by proteolytic cleavage, into Endothelin, the most potent and long lasting endothelium derived contracting factor identified up to date. The intervention of a specific, yet unknown, protease has been evoked. The determination of bigET tertiary structure will contribute to elucidate its proteolytic conversion. In-vitro experimental data on proteolytic fragmentation of bigET in the presence of known proteases and protein homogenates from endothelial cells have been considered for testing the proposed structure.

1991 - Conformational analysis, molecular modeling and quantitative structure-activity relationships studies of 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline α1-adrenergic antagonists [Articolo su rivista]
Rastelli, Giulio; Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

Conformational analysis (AM1), modeling of the molecular shape (QUANTA 3.0) and quantitative structure-activity relationship analysis were done on a set of 16 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline alpha-1-adrenoceptor antagonists (prazosin analogs). The results obtained show that the 2-substituents of the analogs considered are quite flexible. Furthermore, they suggest that, once the electronic requirements of the common quinazoline moiety are satisfied, the binding affinities are modulated by the molecular shape of the quinazoline 2-substituent, through the optimization of both dispersive and steric interactions and the hydrophobic contribution.

1991 - Correlation and Multivariate Analyses of the Spectroscopic Data in 4'-Substituted 4-Nitro-difhenylsulfones [Articolo su rivista]
Cocchi, Marina; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular descriptors such as quantum chemical indices, substituent constants, substituent chemical shifts values of monosubstituted benzenes, and different data analyses (linear regression, dual substituent parameters, and multivariate analysis) have been comparatively used in order to rationalize the electronic substituent effects and to predict C-13 nuclearmagnetic resonance (NMR) and vibrational spectroscopy (IR) data of the 14 title compounds. The results have been compared with those previously obtained for the biologically active 4'-substituted 4-aminodiphenylsulfones, inhibitors of the dihydropteroate synthase enzyme. Both the 4-nitro and the 4-amino sulfone series show similar transmission of the electronic substituent effects through the C(1)-SO2-C(1') moiety by a hyperconjugative mechanism. Good predictions of the spectroscopic data are obtained with the different models considered. However, the partial least-squares method and principal componenent analysis seem to be the most powerful predictive tools.

1991 - Direct and Indirect Theoretical QSAR Modelling in Sulfonamide Carbonic Anhydrase Inhibitors [Abstract in Atti di Convegno]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Direct and Indirect Theoretical QSAR Modelling in Sulfonamide Carbonic Anhydrase Inhibitors

1991 - MOLECULAR-ORBITAL STUDY OF THE NITROGEN BASICITY OF PRAZOSIN ANALOGS IN RELATION TO THEIR ALPHA-1-ADRENOCEPTOR BINDING-AFFINITY [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Rastelli, Giulio; Cocchi, Marina
abstract

AM1 theoretical molecular descriptors were computed for prazosin analogues (2-substituted 4-amino-6,7-dimethoxy derivatives of quinazoline, quinoline and isoquinoline) and and correlated with both their experimental acidity constants and alpha-1-adrenoceptor binding affinity data values. The results confirm the crucial role of the N1 protonated form of these derivatives for a selective and productive binding interaction with the alpha-1 adrenergic receptor.

1991 - QSAR Analysis Using Theoretical Molecular Descriptors in 2,4-Diamino-6,7-Dimethoxy Quinazoline 1-Adrenoceptor Antagonists. [Abstract in Atti di Convegno]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Rastelli, Giulio; Cocchi, Marina
abstract

QSAR Analysis,Theoretical Molecular Descriptors,Quinazoline,a1-Adrenoceptor Antagonists.

1991 - Theoretical conformational analysis, electronic structure and molecular modelling studies in dihydropteroate synthase in hibition by multisubstituted s [Articolo su rivista]
Sokolov, Yu. A.; Menziani, M. C.; Cocchi, M.; De Benedetti, P. G.
abstract

Theoretical conformational analysis (MNDO) has been performed for six selected 4-aminoaryl multisubstituted aryl sulphones (4'-NH2; 2',4'-Cl2; 2',4',6'-Cl3; 2'-OH, 4'-O-; 2'-Cl, 4'-O-; 2'-CH3,4'-O-) which are competitive inhibitors, with respect to the substrate 4-aminobenzoate, of the dihydropteroate synthase. These derivatives show multiple conformational energy minima mainly due to the torsional freedom of the sulphur-carbon bond (θ2) of the substituted aryl ring. The other sulphur-carbon torsional angle considered (θ1), lying on the biofunctional common moiety 4-NH2C6H4SO2, is quite rigid, with the aryl ring perpendicular to the C1-S-C1' plane (θ1=90 °). The most stable conformera for all the derivatives considered are θ1=90 ° and θ2=90 ° (butterfly conformation) and θ1=90 ° and θ2=60 °. The highly active derivatives are, in general, less flexible and the inhibitory potency of the six sulphones considered is rationalized in terms of the electronic features of their common moiety, which do not significantly change among the different conformera of the same derivative. Finally, a good matching was obtained by computer superposition between the substrate 4-NH2C6H4COO- and the biofunctional common moiety 4-NH2C6H4SO2 of the sulphones. © 1991.

1990 - QSAR analysis in 2,4-diamino-6,7-dimethoxy quinoline derivatives - α1-adrenoceptor antagonists - using the partial least squares (PLS) method and theoretical molecular descriptors [Articolo su rivista]
Cocchi, Marina; Menziani, Maria Cristina; Rastelli, Giulio; DE BENEDETTI, Pier Giuseppe
abstract

QSAR analysis in 2,4-diamino-6,7-dimethoxy quinoline derivatives - α1-adrenoceptor antagonists - using the partial least squares (PLS) method and theoretical molecular descriptors

1989 - A Theoretical Study of Conformation-Electronic Structure Relationships in Benzensulfonamide Inhibitors of Carbonic Anhydrase Enzyme. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Frassineti, Chiara
abstract

A Theoretical Study of Conformation-Electronic Structure Relationships in Benzensulfonamide Inhibitors of Carbonic Anhydrase Enzyme.

1989 - Comparative QSAR Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Design of Some New Derivatives with Improved Petency. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; Cocchi, Marina; Cennamo, Carlo
abstract

Comparative QSAR Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Design of Some New Derivatives with Improved Petency.

1989 - Quantitative Structure-Activity Relationships in Dihydropteroate Synthase Inhibition by Multisubstituted Sulfones. Design and Synthesis of Some New Derivatives with Improved Potency. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Folli, Ugo; Frassineti, Chiara; Menziani, Maria Cristina; Cennamo, Carlo
abstract

Quantitative Structure-Activity Relationships in Dihydropteroate Synthase Inhibition by Multisubstituted Sulfones. Design and Synthesis of Some New Derivatives with Improved Potency.

1989 - The binding of benzenesulfonamides to carbonic anhydrase enzyme. A molecular mechanics study and quantitative structure-activity relationships [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; F., Gago; W. G., Richards
abstract

Molecular mechanics methods have been applied to study the interaction between a series of 20 deprotonated benzenesulfonamides and the enzyme carbonic anhydrase. The different contributions to the binding energy have been evaluated and correlated with experimental inhibition data and molecular orbital indices of the sulfonamides in their bound conformation. The results suggest that the discrimination shown by the enzyme toward these inhibitors is dominated by the short-range van der Waals forces

1988 - Multinuclear NMR and Vibrational Spectroscopy Studies of the Substituent Effects in Benzensulfonamide Inhibitors of the Enzyme Carbonic Anhydrase. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Menziani, Maria Cristina; Frassineti, Chiara; Benedetti, Adriano
abstract

Multinuclear NMR and Vibrational Spectroscopy Studies of the Substituent Effects in Benzensulfonamide Inhibitors of the Enzyme Carbonic Anhydrase.

1987 - A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Frassineti, Chiara
abstract

A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides.

1987 - Quantitative Structure-Activity Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Comparison with Sulfanilamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Menziani, Maria Cristina; V., Caiolfa; Frassineti, Chiara; Cennamo, Carlo
abstract

Quantitative Structure-Activity Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Comparison with Sulfanilamides.

1985 - A Quantum Chemical QSAR Study of Carbonic Anhydrase Inhibition by Sulfonamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Frassineti, Chiara
abstract

A Quantum Chemical QSAR Study of Carbonic Anhydrase Inhibition by Sulfonamides.

1985 - Experimental and Theoretical Study of Electronic Substituent Effects in 4-Aminoaryl (4-Substituted Aryl) Sulphones. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Folli, Ugo; Iarossi, Dario; Frassineti, Chiara
abstract

Experimental and Theoretical Study of Electronic Substituent Effects in 4-Aminoaryl (4-Substituted Aryl) Sulphones.

1983 - A Theoretical Study of the Structure-Activity Relationship in Diarylsulphones. Comparison with Sulfa Drugs. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Frassineti, Chiara
abstract

A Theoretical Study of the Structure-Activity Relationship in Diarylsulphones. Comparison with Sulfa Drugs.

1981 - Structure-Activity Relationship in Dihydropteroate Synthase Inhibition by Sulfanilamides. Comparison with the Antibacterial Activity. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Rastelli, Augusto; Frassineti, Chiara; Cennamo, Carlo
abstract

Structure-Activity Relationship in Dihydropteroate Synthase Inhibition by Sulfanilamides. Comparison with the Antibacterial Activity.

Università degli studi di Modena e Reggio Emilia

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