Molecular modelling analysis of the metabolism of entecavir

Abstract

In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to investigate the relative stability of ETV and its metabolites with the aim of providing a better understanding of their relative toxicity. The results of the analyses show that both ETV and its major metabolites have LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surface of ETV is found to posses neutral, electron-rich and electron-deficient regions so that the compounds may be subjected to lyophilic, electrophilic and nucelephilic attracks. Nucleophilic attacks can be due to cellular nucleophiles such as glutathione and nucleobases in DNA. However, because of the kinetic inertness of the molecules the rates of such adverse reactions are expected to be low so that ETV and its metabolites may not cause high toxicity. © 2008 Academic Journals Inc.