Towards Development of a Computational Screening Tool for Quinone Oxidoreductase Inhibitors

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) and its paralog NRH:quinone oxidoreductase 2 (NQO2) function by reducing quinones into hydroquinones via a two-electron reduction, which is mediated by the cofactor flavin adenine dinucleotide (FAD). These enzymes also catalyze a similar reduction of nitroaromatic compounds to produce cytotoxic drugs. This study details the development of a computational protocol designed to screen many molecules in order to accurately predict the binding orientations of various small aromatic molecules to NQO1 and NQO2. The protocol consists of geometric positioning of molecules on the flavin ring, calculating binding free energy, and scoring these ligand molecules bound to the active site. Electronic structure calculations were performed on small model system. In parallel, a larger model with enzyme was built up and treated by a hybrid quantum mechanical/molecular mechanical approach. This was done by applying approximated quantum mechanics only to the flavin ring and ligand atoms. The computational setup and preliminary results including the binding energies and predicted orientations is presented.