Abstract
Molecular modeling and MTD methods are useful tools to assess both qualitative(SAR) and quantitative (QSAR) chemical structure-biological activity relationships. The 1-[(2-hydroxiethoxi)-methyl]-6-(phenylthio)thymine congeners (HEPT ligands) show in vitroanti-viral activity against the type-1 human immunodeficiency virus (HIV-1), which is theetiologic agent of AIDS. This work shows an extensive QSAR study performed upon a largeseries of 79 HEPT ligands using the MTD and HyperChem molecular modeling methods.The studied HEPT ligands are HIV reverse-transcriptase inhibitors. Their geometries wereoptimized and conformational analysis was carried out to build the hypermolecule, whichallowed applying the MTD method. The hypermolecule was used for space mapping of thereceptor’s interaction site. The obtained results show that there are three 3D molecular zonesimportant for the anti-HIV biological activity of the HEPT ligands under study.
Highlights
The acquired immunodeficiency syndrome (AIDS) appears due to an infection process with viral agents belonging to the retrovirus family: human immunodeficiency viruses 1 (HIV-1) and 2 (HIV-2) [1, 2]
Our research is focused on quantitative chemical structure – biologic activity studies based on a 3D method, the Minimal Topological Difference method (MTD)
Molecular modeling is not able to give a quantitative prediction upon biological activity; it can deliver very useful data in order to design new molecular structures with increased bioactive potential [24]
Summary
The acquired immunodeficiency syndrome (AIDS) appears due to an infection process with viral agents belonging to the retrovirus family: human immunodeficiency viruses 1 (HIV-1) and 2 (HIV-2) [1, 2]. Our research is focused on quantitative chemical structure – biologic activity studies based on a 3D method, the Minimal Topological Difference method (MTD) This method, beyond the improved correlation equation delivers a structural stereochemical requirement necessary for an optimal HEPT ligand attack estimation on the HIV-1 virus. These positions, together with the bonds between them, form a so called “hyperstructure” with both topological and geometrical connotations In this context, let’s consider N molecules Li (I=1, 2,..., N) with known activities Ai for which we wish to obtain a structure-activity correlation equation so that to pose minimum steric/topologic differences MTDi as a quantitative degree of their misfit with the receptor’s cavity [15].
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