Virtual Screening, Molecular Docking, and Dynamic Simulations Revealed TGF-ß1 Potential Inhibitors to Curtail Cervical Cancer Progression.

Cervical cancer is one of the main causes of cancer death in women globally, and its epidemiology is similar to that of a low-infectious venereal illness. Many sexual partners and early age at first intercourse have been demonstrated to have a significant influence on risk. TGF-ß1 is a multifunctional cytokine that is required for cervical carcinoma metastasis, tumor development, progression, and invasion. The TGF-ß1 signaling system plays a paradoxical function in cancer formation, suppressing early-stage tumor growth while increasing tumor progression and metastasis. Importantly, TGF-ß1 and TGF-ß receptor 1 (TGF-ßR1), two components of the TGF-ß signaling system, are substantially expressed in a range of cancers, including breast cancer, colon cancer, gastric cancer, and hepatocellular carcinoma. The current study aims to investigate possible inhibitors targeting TGF-ß1 using molecular docking and dynamic simulations. To target TGF-ß1, we used anti-cancer drugs and small molecules. MVD was utilized for virtual screening, and the highest scoring compound was then subjected to MD simulations using Schrodinger software package v2017-1 (Maestro v11.1) to identify the most favorable lead interactions against TGF-ß1. The Nilotinib compound has shown the least XP Gscore of -2.581 kcal/mol, 30ns MD simulations revealing that the Nilotinib- TGF-ß1 complex possesses the lowest energy of -77784.917 kcal/mol. Multiple parameters, including Root Mean Square Deviation, Root Mean Square Fluctuation, and Intermolecular Interactions, were used to analyze the simulation trajectory. Based on the results; we conclude that the ligand nilotinib appears to be a promising prospective TGF-ß1inhibitor for reducing TGF-ß1 expression ad halting cervical cancer progression.

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

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.