Pharmacophore Modeling, Virtual Screening, Molecular Docking, Synthesis, 3D-QSAR Studies, Anti-cancer Activity and In-silico ADMET Studies of c-MET Receptor Tyrosine Kinase Inhibitors

Abstract

Cancer is very complicated and serious disorder seen in human beings. Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths). Lung, stomach, liver, colon and breast cancer cause the most cancer deaths each year. About 30% of cancer deaths are due to the five leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, alcohol use.One of the most important therapeutic targets with its aberrant signaling mediating invasive cellular program in cancers is c-MET Receptor Tyrosine Kinase. c-MET pathway is responsible for triggering various signaling pathway like RAS-MAPK pathway, PI3K pathway, STAT3/5 pathway and ALK pathway. c-MET triggers tumor growth, formation of new blood vessels that supply the tumor with nutrients, and cancer spread to other organs. in this present studies, computational followed by synthetic approaches were used to design and evaluate small molecules targeting c-MET kinase. The generation of pharmacophore was carried out using PHASE and GALAHAD modules of two different software in order to identify essential features required to be present in c-MET kinase inhibitors. All the generated models of pharmacophore were validated using required validation protocol. The best model was subjected to virtual screening in which about 18000 molecules were retrieved. 3D-QSAR studies were performed on a potent series of pyrollotriazine targeting c- MET kinase. The results of 3D-QSAR was found to be acceptable. Around 25 molecules were designed having pyrazole ring and docked onto respective c-MET kinase. Among 25 molecules, 10 molecules had shown acceptable docking results. Out of 10 molecules, 4 molecules were synthesized and characterized using physical and spectral properties. Insilico ADMET were done to predict the pharmacokinetic and toxicity profile of synthesized molecules. The anti-cancer activity was executed on MCF-7, HCT-15, A-375 cell lines respectively.