Héctor A. Baldoni

Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration.

A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC₅₀ values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.

An exploratory ab initio study of the full conformational space of N-acetyl-l-cysteine-N-methylamide

Abstract The full conformational space of N -acetyl- l -cysteine- N -methylamide was explored by ab initio MO computations. On the Ramachandran hypersurface of four independent variables E = E ( φ , ψ , χ 1 , χ 2 ), 47 conformers were located instead of the expected 3 4 =81 stable structures. The relative stabilities of the various conformers were analyzed in terms of side-chain–backbone interactions covering both hydrogen bonding and charge-transfer types. The stabilization energies exerted by the side-chain of cysteine on the backbone were compared to those of other amino acids.

Peptide models XXIX. cis-trans Isomerism of peptide bonds: ab initio study on small peptide model compound; the 3D-Ramachandran map of formylglycinamide

Thermodynamic separations for cis and trans-amides and formylglycinamide range from 0.00 to 4.77 kcal/mol as computed at various levels of theory. The barriers for trans! cis-isomerization, for the same set of compounds, computed at various levels of theory, were found between 15.69 and 22.67 kcal/mol. The cis- and trans-Ramachandran maps of formylglycinamide are compared and the topology of the ab initio 3D-Ramachandran map is presented for the first time.q 2000 Elsevier Science B.V. All rights reserved.

Characteristics of Ramachandran maps of L-alanine diamides as computed by various molecular mechanics, semiempirical and ab initio MO methods. A search for primary standard of peptide conformational stability

Abstract The optimized geometries and relative energies obtained by four force field and two semi-empirical methods were compared with ab initio results computed for formyl- L -alaninamide. Not all methods yielded the same number of minimum energy conformers. Furthermore, while the optimized geometries of the conformers found were comparable, the computed relative energies varied substantially. Also, the force field calculations produced Ramachandran maps that did not even have the appearance of the ab initio Ramachandran map. Correlating the ab initio relative energies (Δ E ) or free energy (Δ G ) with the log of relative populations, ln( p x / p γ L ), led to linear relationships from which four conformers deviated; two of them (α L and e L ) were overly destabilized and two of them (γ L and γ D ) were over-stabilized. It is suggested that, after such deviations are corrected, a primary standard may be obtained that might be useful in further investigations related to force-field parametrization as well as protein folding.

Peptide Models XXXVIII. Proline conformers from X-ray crystallographic database and from ab initio computations

Abstract A systematic comparison is made between experimental and computational data gained on l -proline in peptides. Data on 214 XPY type amino acid sequence units taken from the Cambridge Structural Database as well as ab initio calculations on the model peptide HCO- l -Pro-NH 2 at the 3-21G and 6-31+G(d) RHF levels of theory are presented. Cis – trans isomerism, backbone conformation and ring puckering are studied. Ring puckers are characterized by pseudorotational coordinates. A convenient nomenclature of conformers is introduced. Population data gained directly from statistics and derived from energy calculations are also discussed.

Structural and Thermodynamic Characteristics of the Exosite Binding Pocket on the Human BACE1: A Molecular Modeling Approach

We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within 6 Å from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1−INH complex.

Looking for the interactions between omeprazole and amoxicillin in a disordered phase. An experimental and theoretical study.

In this paper, co-grinding mixtures of omeprazole-amoxicillin trihydrate (CGM samples) and omeprazole-anhydrous amoxicillin (CGMa samples) at 3:7, 1:1 and 7:3 molar ratios, respectively, were studied with the aim of obtaining a co-amorphous system and determining the potential intermolecular interactions. These systems were fully characterized by differential scanning calorimetry (DSC), FT-infrared spectroscopy (FTIR), X-ray powder diffraction (PXRD), scanning electron microscopy (SEM) and solid state Nuclear Magnetic Resonance (ssNMR). The co-grinding process was not useful to get a co-amorphous system but it led to obtaining the 1:1 CGMa disordered phase. Moreover, in this system both FTIR and ssNMR analysis strongly suggest intermolecular interactions between the sulfoxide group of omeprazole and the primary amine of amoxicillin anhydrous. The solubility measurements were performed in simulated gastric fluid (SGF) to prove the effect of the co-grinding process. Complementarily, we carried out density functional theory calculations (DFT) followed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses in order to shed some light on the principles that guide the possible formation of heterodimers at the molecular level, which are supported by spectroscopic experimental findings.

A theoretical study on the conformations of azadirachtin

Abstract The conformation and the charge distribution of azadirachtin were analysed using molecular mechanics and AM1 calculations. The present paper reports our computational efforts that aim to characterise the skeletal conformational behaviour of azadirachtin and to determine the conformational flexibility of the functional groups present in the molecule. Intramolecular interactions related to the electronic structure of the molecule are also discussed. In addition, a comparative analysis of the conformational characteristics of azadirachtin and its related methyl ether derivatives was included in our study. A critical examination of the functional groups present in azadirachtin and their methyl ether derivatives provide us with crucial information about the optimal relative conformation required to stimulate an antifeedant response. On the basis of our results, it is reasonable to conclude that the highly preferred conformation obtained for azadirachtin could play a significant role in the stimulation of biological activity.

Theoretical study on the conformations of 3-tigloyl-azadirachtol and azadirachtin derivatives

Abstract Conformational and electronic studies of 3-tigloyl-azadiractol and other azadirachtin derivatives were carried out using molecular mechanics and AM1 calculations. A comparative analysis of the conformational characteristics of 3-tigloyl-azadirachtol, azadirachtin and its structurally related derivatives was also performed. Our results indicate that the lack of antifeedant activity of 7-ketoazadirachtin and other inactive compounds can be explained on the basis of their different conformational behaviour. The conformationally restricted azadirachtin analogues provide us with crucial information about the optimal conformational requirement necessary to stimulate an antifeedant response.

Essential Dynamics on Different Biological Systems: Fis Protein, tvMyb1 Transcriptional Factor and BACE1 Enzyme

Proteins and enzymes poses a non-covalent 3D structure and therefore their intrinsic flexibility allows the existence of an ensemble of different conformers which are separated by low-energy barriers. These ranges of available conformers for proteins in solution are due to the relative movements among the different domains. Domain motions are important for a variety of protein functions, including catalysis, regulation of activity, transport of metabolites, formation of protein assemblies, and cellular locomotion.