Abstract

Drug Metabolism and Toxicity Studies Using Theoretical Chemistry Methods

Prasad Bharatam, Professor, NIPER Mohali

Compounds containing methylenedioxyphenyl (MDP) moiety lead to the Mechanism-Based Inactivation (MBI) of cytochrome P450 (CYPs) by undergoing biotransformation to the reactive carbene intermediate. This carbene coordinates with the heme iron, forming metabolic-intermediate complex (MIC), resulting in quasi-irreversible inhibition of CYPs. The bioinorganic chemistry of the RMs (carbenes) and their implications in toxicity have been explored thoroughly, using Density Functional Theory (DFT). Quantum chemical analysis was carried out to (i) analyze the characteristics of MDP-carbene in terms of singlet-triplet energy difference, protonation and dimerization energies, etc., (ii) determine the electronic structure and stability of MIC, and elucidate the reaction pathway leading to the formation of reactive carbene intermediate, using Cpd I (iron(IV)-oxo-porphine) as the model oxidant. MDP-carbenes lead to the formation of stable MIC (-40.35 kcal/mol) on the doublet spin state, formed via interaction between sLP of carbene and empty dz2 orbital of heme-iron. Three alternative pathways were proposed and explored.