Design and Synthesis of Novel Scanffold as B-Raf Kinase Inhibitor the Treatment of Skin Cancer

Abstract

Cancer is the second leading cause of death after cardiovascular disease. Melanoma is more aggressive than most other types of cancer. B-Raf belongs to the serine/threonine kinase family playing an essential role in cell growth proliferation. Almost 70% B-Raf mutation found in melanoma cancer. Hence, B-Raf is the excellent target for the treatment of melanoma cancer. To design novel B-Raf kinase inhibitors, various computational approaches like pharmacophore modelling, virtual screening, 3D-QSAR (CoMFA, CoMSIA, HQSAR, and Topomer CoMFA) and molecular docking were use. Pharmacophore model was generated using 10 structurally diverse molecules using DiscoTech module and best-generated model was refined with GASP module of Sybyl X. The refined best pharmacophore model with nine features; one hydrophobic region, three donor sites, three acceptor atom, one donor atom, and one acceptor site, was used as a query for virtual screening in the NCI database. Virtual hits from NCI database was further screened by applying the Lipinski’s filter, removal of counter ions / duplicate structures that resulted into 11485 hits. 3D-QSAR study was also performed on purinyl-pyridine derivatives. Benzoxazole moiety was selected from features of best pharmacophoric model and bioisosteric replacement of core ring of virtual hit molecules, while various substitutes were incorporate based upon contour map analysis of 3D-QSAR studies. Molecular docking study of novel benzoxazole derivatives were carried out by using GOLD 5.2. Among, all designed molecules, few compounds showing good docking score as compared to the marketed available B-Raf inhibitor, Vemurafenib, were synthesized and characterised. All synthesized molecules were evaluated for in vitro cytotoxicity studies on various cell lines and potent molecule is under investigation for in vivo pharmacological models for skin cancer. In future, this study will be explored to develop hit to lead generation of novel inhibitor against mutated B-Raf for effective skin cancer therapy