Papers by Maria Cristina Menziani
α1-Adrenoceptor subtype selectivity: Molecular modelling and theoretical quantitative structure—affinity relationships
Bioorganic & Medicinal Chemistry, 1997
ABSTRACT This study constitutes a preliminary rationalization, at the molecular level, of antagon... more 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.
Theoretical quantitative structure—activity relationship analysis on three dimensional models of ligand—m1 muscarinic receptor complexes
Bioorganic & Medicinal Chemistry, 1994
The heuristic-direct QSAR (quantitative structure-activity relationships) approach has been appli... more The heuristic-direct QSAR (quantitative structure-activity relationships) approach has been applied to a series of 34 muscarinic receptor ligands, including antagonists, weak partial agonists, partial agonists and full agonists, interacting with the human ml-muscarinic receptor subtype. The first step of this procedure consists of the computer-aided 3D-model building of the receptor. The second step involves docking simulations with selected ligands, maximizing the complementarity between ligand and receptor. In the third step, a detailed and extensive correlation analysis between the computed interaction energies, their components and the experimental pharmacological affinity and action is accomplished in order to evaluate the consistency of the QSAR model proposed and to provide a quantitative tool for comparisons among the different complexes considered. In this context, good linear correlations have been obtained between ad hoc theoretical intermolecular interaction descriptors and the pharmacological action, which allow one to classify quantitatively and predict the pharmacological action of new ligands. Finally, according to the ml-receptor model proposed, it has been possible to speculate on the amino acid residues which are mainly involved in the interaction with the ligands, and on the nature of the prevailing intermolecular interactions which are responsible for the different behaviour of antagonists, weak partial agonists, partial agonists and full agonists.
Quantitative Structure-Activity Relationships, 1987
Molecular orbital (MO) indices were computed (CNDO/ 2) for a wide series of heterocyclic (thiadia... more Molecular orbital (MO) indices were computed (CNDO/ 2) for a wide series of heterocyclic (thiadiazole, thiazole, and thiophene) sulfonamide inhibitors of the zinc-enzyme carbonic anhydrase.
Confortnational analysis for 24 arylpiperazines in their neutral and NJ-protonated forms has been... more Confortnational analysis for 24 arylpiperazines in their neutral and NJ-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-HTIA 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 S-HT IA 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-HTIA receptor binding site. 0 1997 Elsevier Science B.V.
Journal of Molecular Structure: THEOCHEM, 1989
0166-1280/89/$03.50 0 1989 Elsevier Science Publishers B.V.
Conformational analysis, molecular modeling and quantitative structure-activity relationship studies of 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline α1-adrenergic antagonists
Journal of Molecular Structure: THEOCHEM, 1991
Conformational analysis (AM1), modeling of the molecular shape (spquanta)3.0) and quantitative st... more Conformational analysis (AM1), modeling of the molecular shape (spquanta)3.0) and quantitative structure-activity relationship analysis were done on a set of 16 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline α 1 -adrenoceptor antagonists (prazosin analogs). The results ...
Journal of Molecular Structure: THEOCHEM, 1992
Quantitative structureactivity relationship analysis using theoretical molecular descriptors was ... more Quantitative structureactivity relationship analysis using theoretical molecular descriptors was done on a set of 30 1,4-benzodioxan (WB-4101) related compounds which are a,-adrenoceptor antagonists. The results obtained confirm quantitatively and in terms of reactivity and molecular shape descriptors, the results of previous qualitative structureactivity relationship studies. It was found that the protonated amine function plays a crucial role in the potency of the a,-adrenoceptor antagonism due to a charge reinforced hydrogen bond with a primary nucleophilic site of the receptor. Furthermore, the more electrophilic (high SNILuMo values) the NH,' 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 (ELuM,-,) and the ad hoc shape (V,(norm)) descriptors were used to obtain a bilinear equation which accounts for about 77% of the total variance in the pharmacological data.
The heuristic-direct approach to theoretical quantitative structure-activity relationship analysis of< i> ��</i>< sub> 1</sub>-adrenoceptor ligands
ABSTRACT
The Journal of Physical Chemistry B, 2005
The results of a qualitative and quantitative structure-property relationships analysis of multic... more The results of a qualitative and quantitative structure-property relationships analysis of multicomponent potential bioglasses of composition (2y)SiO 2 ‚1Na 2 O‚1.1CaO‚yP 2 O 5 ‚xZnO (x ) 0, 0.16, 0.35, 0.78 and y ) 0.10, 0.20, 0.36) are presented. Quantitative models are obtained by means of structural descriptors derived by molecular dynamics simulations and experimental data measured for density, thermal analysis, 29 Si and 31 P magic angle spinning NMR, and chemical durability in water. Analysis of the crystal species obtained upon glass crystallization helped in the rationalization of the structural role of the different components. Finally, glass surface characterization with scanning electron microscopy, transmission electron micrsocopy, and X-ray diffraction after soaking in acellular simulated body fluid demonstrated the in vitro bioactivity of the newly obtained 1.80SiO 2 ‚1Na 2 O‚1.1Ca‚0.20P 2 O 5 ‚0.16ZnO (HP5Z5) glass, corresponding to x ) 0.16 and y ) 0.20. * Corresponding authors. E-mail: menabue@unimo.it (L.M.); menziani@unimo.it (M.C.M.). Tel.: +39 059 2055042 (L.M.); +39 059 2055091 (M.C.M.). Fax: +39 059 373543 (L.M.); +39 059 373543 (M.C.M.).
A combined experimental and computational approach to (Na2O)1−x·CaO·(ZnO)x·2SiO2 glasses characterization
Journal of Non-Crystalline Solids, 2004
Insight into the Zn structural role in a series of glasses of composition (Na2O)1−x·CaO·(ZnO)x·2S... more Insight into the Zn structural role in a series of glasses of composition (Na2O)1−x·CaO·(ZnO)x·2SiO2 (x=0, 0.2, 0.6 and 1) has been obtained by density measurements, analysis of the crystals separated from the glasses, micro-Raman spectra and molecular dynamics simulations. We found that Zn acts as a weak tetrahedral network former independent of the glass Na content.
Objective. To characterize the topographic and chemical properties of 2 bioceramic coated plateau... more Objective. To characterize the topographic and chemical properties of 2 bioceramic coated plateau root form implant surfaces and evaluate their histomorphometric differences at 6 and 12 weeks in vivo. Methods. Plasma sprayed hydroxyapatite (PSHA) and amorphous calcium phosphate (ACP) surfaces were characterized by scanning electron microscopy (SEM), interferometry (IFM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). Implants were placed in the radius epiphysis, and the right limb of dogs provided implants that remained for 6 weeks, and the left limb provided implants that remained 12 weeks in vivo. Thin sections were prepared for bone-to-implant contact (BIC) and bone-area-fraction occupancy (BAFO) measurements (evaluated by Friedman analysis P < 0.05). Results. Significantly, higher S a (P < 0.03) and S q (P < 0.02) were observed for ACP relative to PSHA. Chemical analysis revealed significantly higher HA, calcium phosphate, and calcium pyrophosphate for the PSHA surface. BIC and BAFO measurements showed no differences between surfaces. Lamellar bone formation in close contact with implant surfaces and within the healing chambers was observed for both groups. Conclusion. Given topographical and chemical differences between PSHA and ACP surfaces, bone morphology and histomorphometric evaluated parameters showed that both surfaces were osseoconductive in plateau root form implants.
An extensive benchmarking of exchange-correlation functionals, pseudopotentials, and basis sets o... more An extensive benchmarking of exchange-correlation functionals, pseudopotentials, and basis sets on real X-ray resolved nanoclusters has been carried out and reported here for the first time. The systems investigated and used for the tests are two undecagold and one Au + 24 -based nanoparticles stabilized by thiol and phosphine ligands. Time-dependent density-functional calculations have been performed for comparing results with experimental data on optical gaps. It has been observed that GGA functionals employing PBE-like correlation (viz. PBE itself, BPBE, BP86, and BPW91) coupled with an improved version of the LANL2DZ pseudopotential and basis set provide fairly accurate results for both structure and optical gaps of gold nanoparticles, at a reasonable computational cost. Good geometries have been also obtained using some global hybrid (e.g. PBE0, B3P86, B3PW91) and range separated hybrid (e.g. HSE06, LC-BLYP) functionals, even though they yield optical gaps that constantly overestimate the experimental findings. To probe the effect of the stabilizing organic ligands on the structural and electronic properties of the metal core, we have simulated the full metalorganic nanoparticles (whose diameter exceed the 2 nm threshold) with an ONIOM QM/QM' approach and at the density-functional level of theory. This work represents a first step toward the simulations of structural and opto-electronic properties of larger metal-organic particles suitable for a wide range of nanotechnological applications.
Journal of Physical Chemistry B, 2001
Changes in the structural properties of sodium alumino-silicate glasses of general formula Na 2 O... more Changes in the structural properties of sodium alumino-silicate glasses of general formula Na 2 O‚xAl 2 O 3 ‚(3x)SiO 2 were investigated as a function of Al 2 O 3 concentration. The experimental evidences provided by density, elastic modulus, glass chemical resistance measures, 29 Si and 27 Al MAS NMR investigations were complemented by molecular dynamics simulations. While neither of the experimental techniques or computational investigation utilized in this study were able to furnish unequivocable responses for the rationalization of the measured properties of sodium alumino-silicate glasses, the synergistic application of experimental and computational techniques showed that the anomalies observed in bulk properties like density and elastic modulus find their origin in medium-range structural features.
Synthesis, Characterization, and Molecular Dynamics Simulation Of Na 2 O−CaO−SiO 2 −ZnO Glasses
Journal of Physical Chemistry B, 2002
ABSTRACT The glass of composition Na2O.CaO.2SiO(2) was modified upon addition of ZnO to obtain th... more ABSTRACT The glass of composition Na2O.CaO.2SiO(2) was modified upon addition of ZnO to obtain the series of glasses Na2O.CaO.2SiO(2).xZnO (x = 0.17, 0.34, 0.68), where x = 0.68 is the experimentally determined maximum zinc content that does not produce phase separation. The glasses were investigated by means of density and thermal measurements (,(glass-transition and crystallization temperatures); moreover, the phases separated upon crystallization were identified. The results of molecular dynamics (MD) simulations combined with the analysis of the crystal structure of the main phases separated (Na2Ca(SiO3)(2) and Na2ZnSiO4) provided insights into the structural role of zinc and its effect on the short- and medium-range order of the glass structures.
Control of Metalloprotein Reduction Potential: Compensation Phenomena in the Reduction Thermodynamics of Blue Copper Proteins †
Biochemistry, 2003
The changes in the thermodynamics of Cu(II) reduction for spinach plastocyanin induced by point m... more The changes in the thermodynamics of Cu(II) reduction for spinach plastocyanin induced by point mutations altering the electrostatic potential in proximity of the copper center were determined through variable temperature direct electrochemistry experiments. In particular, the functionally important surface residues Leu12 and Gln88 were replaced with charged and polar residues, and Asn38 was substituted with Asp. The mutational variations of the reduction enthalpy and entropy were analyzed with a QSPR (quantitative structure-property relationships) approach, employing global and local theoretical descriptors defined and computed on the three-dimensional protein structure. The correlations found are informative on how electrostatic and solvation effects control the E degrees &#39; values in this species through the combined effects on the reduction enthalpy and entropy. The changes in reduction enthalpy can be justified with electrostatic considerations. Most notably, enthalpy-entropy compensation phenomena play a significant role: the entropic effects due to the insertion of charged residues determine E degrees &#39; changes that are invariably opposite to those induced by the concomitant enthalpic effects. Therefore, the resulting E degrees &#39; changes are small or even opposite to those expected on simple electrostatic grounds. The mutational variation in the reduction entropy appears to be linked to the hydrogen bonding donor/acceptor character of the northern part of the protein, above the metal site, and to the electrostatic potential distribution around the copper site. Both properties influence the reduction-induced reorganization of the water molecules on the protein surface in the same region.
Molecular orbital study of the nitrogen basicity of prazosin analogues in relation to their ��< sub> 1</sub>-adrenoceptor binding affinity
ABSTRACT
Journal of Molecular Structure-Theochem, 2000
Among the ligand design methods based on the theoretical QSAR paradigm, the simple ad hoc supermo... more 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. ᭧
Molecular Informatics, 2012
The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Ana... more The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TSdomain on the S1' loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases.
Sequence-directed recognition peptides (SDRP) inhibitors of human big endothelin (BigET) proteolysis, molecular design, modeling and dynamics of the BigET-SDRP complexes
Computational simulations of agonist/antagonist interactions with the alpha1-adrenoceptor
Pharmacological Research, 1995
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Papers by Maria Cristina Menziani