Design of Novel Anti-Cancer Agents: Pharmacophore Modeling, Virtual Screening, Molecular Docking, Synthesis, 3d Qsar Studies, Pharmacological Evaluation and In-Silico Admet Studies

Abstract

Cancer can strike people at any age, although they can be diagnosed and can be treated successfully in their early ages. The major problem with cancer therapy is the frequent relapses seen in patients. In order to reduce such relapses it is necessary to develop various therapies that target the cancer site. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. The Aurora kinase family members (A,B and C) are a collection of highly related and conserved serine/threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely liked to chromosomal aneuploidy in cancer cells. In course of my research to discover novel Aurora kinase-A inhibitors, both computational and synthetic approaches were used to design and synthesis of newer agents. Pharmacophore mapping was performed on 11 chemically diverse molecules using GALAHAD. Twenty pharmacophore models were generated and model 5 was considered the best model as it had higher specificity compared to all other models. The best pharmacophore hypothesis contained 5 features including 2 donor sites, 1 acceptor atom and 2 hydrophobic region. Model 6 was used as a query in NCI and Maybridge hit finder databases. A total number of 16829 molecules were obtained after Lipinski filtering. 3D-QSAR studies (CoMFA and CoMSIA) were conducted on a series of 48 compounds . The best prediction were obtained with a CoMFA (q2 = 0.491, r2 = 0.963) and with CoMSIA (q2 = 0.500, r2 = 0.961). Both models were validated by a test set of 10 compounds producing good predictive r2 values of 0.607 and 0.519 respectively. On the basis of pharmacophore modeling, virtual screening and 3D QSAR studies, various molecules were desgined having mercaptopurine ring system as the common core structure and were docked on co-crystal structure of Aurora kinase A (PDB ID: 3K5U) to predict the binding orientation of drug candidates to their protein target. From this, 10 different substituted mercapto-purine derivatives were synthesized and characterized by FTIR, 1HNMR and Mass. Anti-cancer activity was carried out using various cell lines like MCF-7, MCF-7, A-375, DU-145. In-silico ADMET studies were carried out using admetSAR . The designed compounds showed good potential to be anti-cancer agents.