Combined Molecular Modelling And 3D-Qsar Study For Understanding The Inhibition Of Nqo1 By Heterocyclic Quinone Derivatives

A combination of three‐dimensional quantitative structure–activity relationship (3D‐QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π‐stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D‐QSAR analysis. The models derived from Model I and Model III, shown leave‐one‐out cross‐validation correlation coefficients ( q 2 LOO ) of .75 and .73 as well as conventional correlation coefficients ( R 2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients ( r 2 pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D‐QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.