Screening and Identification of Potential iNOS Inhibitors to Curtail Cervical Cancer Progression: an In Silico Drug Repurposing Approach

Abstract

Cervical cancer is the second most common cause of cancer deaths in women worldwide and remains the main reason of mortality among women of reproductive age in developing countries. Nitric oxide is involved in several physiological functions inclusive of inflammatory and immune responses. However, the function of NO in tumor biology is debatable. The inducible NOS (iNOS/NOS2) isoform is the one responsible to maintain the levels of NO, and it exhibits pleotropic effects in various cancers with concentration-dependent pro- and anti-tumor effects. iNOS triggers angiogenesis and endothelial cell migration in tumors by regulating the levels of vascular endothelial growth factor (VEGF). In drug discovery, drug repurposing involves investigations of approved drug candidates to treat various other diseases. In this study, we used anti-cancer drugs and small molecules to target iNOS and identify a potential selective iNOS inhibitor. The structures of ligands were geometrically optimized and energy minimized using Hyperchem software. Molecular docking was performed using Molegro virtual docker, and ligands were selected based on MolDock score, Rerank score, and H-bonding energy. In the study shown, venetoclax compound demonstrated excellent binding affinity to iNOS protein. This compound exhibited the lowest MolDock score and Rerank score with better H-bonding energy to iNOS. The binding efficacy of venetoclax was analyzed by performing molecular docking and molecular dynamic simulations. Multiple parameters were used to analyze the simulation trajectory, like root mean square deviation (RMSD), radius of gyration (Rg), and hydrogen bond interactions. Based on the results, venetoclax emerges to be a promising potential iNOS inhibitor to curtail cervical cancer progression.