Chemical Structure-Biological Activity Models for Pharmacophores' 3D-Interactions

Abstract

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners' (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions.

Keywords: chemical stericity; cross-validation; drug design; hydrophobicity; ligand binding; molecular mechanism; multi-linear correlation; quantitative structure-activity relationship (QSAR); statistical correlation; van der Waals interaction.

Figure 1

The electronic basins (left) and the associated electrostatic potential contours (right) for 4-(5-methylindolyl)-2-methylheptylguanidinothiazole, displaying optimized maximum electrophilic activity by the predicted special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) mechanism action [56]. Green lines correspond with highest occupied molecular orbitals (HOMO), magenta with lowest unoccupied molecular orbitals (LUMO) with the yellow shapes marked as key fragments for chemical frontier reactivity.

Figure 2

1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) structure with superimposition of 79 derivatives with minimum energy conformations; these are (marked in blue, in the center) the possible positions for substituents of the uracil ring; also in blue, we marked the 63 obtained vertices [19]; down arrows and triangles denote those beneficial vertices (attributed to the receptor cavity), up arrows and triangles indicate the detrimental vertices, for the mono-linear and bi-linear MTD analysis of Equations (17) and (19) and the optimized charts (18) and (20), respectively; see the text for further details. Circular colors generally indicate self-corresponding visualization for the molecular group belonging in the hypermolecule.