Molecular Modelling Analysis of the Metabolism of Adefovir Dipivoxil
Adefovir dipivoxil (ADV) is an oral prodrug designed to enhance low intestinal absorption of the anti-viral agent adepovil (PMEA). The pivoxil moieties of ADV are rapidly cleaved to produce PMEA during absorption through the gut wall. After entry into the cell, PMEA is phosphorylated to produce ADMP which is further phosphorylated to form ADDP. The antiviral activity of the drug is based on the capacity of ADDP to preferentially inhibit viral DNA replication with relative sparing of host DNA synthesis. The dose-limiting toxicity of ADV is nephrotoxicity associated with high systemic exposure. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that ADV and its three metabolites PMEAA, ADMP and ADDP have large LUMO-HOMO energy differences so that they all would be kinetically inert. Thus, although the molecules have some electron-deficient regions on their surface so that they could potentially react with glutathione and nucleobases in DNA, the high kinetic inertness of the molecules is believed to provide protection against such adverse reactions.
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