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Asian Journal of Biochemistry

Year: 2008  |  Volume: 3  |  Issue: 2  |  Page No.: 79 - 89

Molecular Modelling Analysis of the Metabolism of Maraviroc

Fazlul Huq

Abstract

Maraviroc (MVC) is a selective CCR5 antagonist with potent activity and favourable pharmacological properties against human immunodeficiency virus type 1 (HIV-1). Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MVC and its metabolites have large LUMO-HOMO energy differences ranging from 5.3 to 5.8 eV, indicating that the compounds would be kinetically inert. The molecular surfaces of all the compounds are found to abound in neutral regions so that they may be subject to lyophilic attacks. The surfaces are also found to possess some electron-rich and electron-deficient regions so that they may be subject to electrophilic and nucleophilic attacks as well. Nucleophilic attacks may be due to glutathione and nucleobases in DNA as a result of which depletion of glutathione and oxidation of nucleobases in DNA may occur. The former would induce oxidative stress and hence cellular toxicity whereas the latter would cause DNA damage. However, because of kinetic inertness of the molecules, the rates of such adverse reactions are expected to be low.

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