Identification of rheochrysin as a potential anti-cancer inhibitor of NAD(P) H quinone oxidoreductase 1 through ensemble virtual screening, molecular dynamics, MM-GBSA and DFT.

NAD(P)H quinone oxidoreductase 1 (NQO1) plays a multifaceted role in humans and its overexpression is associated with several cancers thereby making it a promising target for anticancer therapy. Moreover, the homodimeric NQO1 protein consists of two active sites formed because of the spatial orientation of the individual monomers. Therefore, ensemble virtual screening (eVS) was performed against both the active sites and multiple crystal structures of NQO1 to account for protein flexibility and predict the binding affinities of potential inhibitors. Since natural products show high structural diversity, ADMET adherent molecules from the ZINC natural product (NP) catalogue were selected for eVS. As a result, two NPs (rheochrysin and pulmatin) were identified as the top strong binders across the virtual screening results. These molecules were then subjected to 250 ns molecular dynamics simulations, MM-GBSA and per residue decomposition analysis which indicated that they exhibit stable protein-ligand interactions in the active sites of NQO1 protein. Furthermore, DFT calculations showed that these molecules exhibited higher energy gap indicating that they are stable with low reactivity. The results indicate that the naturally occurring compound rheochrysin (ZINC04098695) found in the traditional medicinal plant Rheum palmatum exhibits lower binding free energy suggesting its inhibitory potential against NQO1.