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.