In silico design of novel diamino-quinoline-5,8‑dione derivatives as putative inhibitors of NAD(P)H:Quinone oxidoreductase 1 based on docking studies and molecular dynamics simulations

Abstract

NAD(P)H:Quinone Oxidoreductase 1 has been proved as a promising therapeutic target in anticancer drug discovery because of its overexpression in various cancerous cells. In this study, we designed a series of diamino-quinoline-5,8‑dione derivatives as potential inhibitors of NQO1 using in silico structure-based molecular design approach. Initially, molecular docking was used to explore key amino acid residues and binding energies at the active site of enzyme. Based on obtained results, compounds A21, A22, C22 and A26, bearing appreciable enzyme binding affinity (ΔG binding between -11.7 and -11.4 kcal. mol−1 and -15.4 and -15.3 kcal. mol−1 by Vina and Vinardo scoring functions, respectively) and orientation towards the active site of NQO1, were selected for 100 ns molecular dynamics (MD) simulation. MD simulation analyses confirmed that NH of His162A and C2-carbonyl of isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor formed important hydrogen bonds, and residues Trp106A and Tyr129B played a key role in the binding affinity via π-π stacking interactions. Eventually, designed compounds’ binding orientation was verified and confirmed by comparison with a set of previously reported NQO1 inhibitors and bioreductive substrates. According to the results of MM-PBSA calculations, these four selected compounds showed lower free binding energies compared to dicoumarol as a well-known native ligand of enzyme indicating their potential inhibitory effect against NQO1. Designed molecules also obeyed drug-likeness rules and exhibited acceptable predictive ADMET properties. These results provide valuable insight for the discovery of new NQO1 inhibitors.