The analysis of NQO1 isoforms as an Off-target to anti-cancer drug RH1 using molecular modeling and structure-based drug discovery approaches

Abstract

NQO1 is already evaluated for its high-level expression in numerous human cancers as compared with normal tissues. RH1 acts as an indigenous prodrug to NQO1. In our preceding work Off-targeting of (RH1) drug to protein kinases is well reported. Numerous protein isoforms have reported a potential drug target and biomarkers in cancer and related diseases. In the present study, the 3D structure of all the three NQO1 isoforms is modelled using the homology based concept, evaluated for their conformational stability and energy forms by MD simulation. MSA and related method used for binding site prediction. Protein-ligand interactions were studied using molecular docking approach. The 3D modelled structure of NQO1 isoform 2 and 3 exhibited a conformational change in the protein FAD and RH1 binding region due to the absence of a few key amino acids. Docking results revealed a good degree of binding energy and interaction between the selected NQO1 isoforms, FAD and RH1. As FAD acts as a floor surface to RH1, a similar trend observed in the NQO1 isoform 2 and 3. Hence the NQO1 isoforms 2 and 3 could be a drug target to anticancer prodrug RH1 and can be further investigated in the lab.