In-silico Designing of Novel Camptothecin Analogues as Potent Inhibitors of Topoisomerase I: A Molecular Docking, QSAR, and ADME-T Study

Abstract

Cancer is the second largest cause of deaths across the globe. The current treatments available for cancer include surgical removal of the infected tissue, radiotherapy, chemotherapy and combinatorial therapeutic approach. Most of the commercially available anti-cancer drugs and their unique modes of action are decoded by the cancer cells, making them less effective. Hence, there is an increasing demand for newer class of drugs with better pharmacological properties and fewer side effects. Camptothecin (CPT), the quinoline alkaloid isolated from Camptotheca acuminata is a wellknown Topoisomerase I inhibitor. It has a proven anti-cancer activity against various cell lines. However, its poor pharmacological properties like low solubility and a narrow therapeutic index calls for better therapeutic alternatives. In this study, eight novel analogues of camptothecin were rationally designed based on the structure-activity relationship of the substituent groups. The designed analogues were further analyzed in-silico for their drug-likeness, quantitative structure-activity relationship (QSAR) and ADME-T properties. All the novel analogues were docked with topoisomerase I using Autodock 4.2 and the docking results were validated with the help of an online docking server, Patchdock. In this study, we have found that the therapeutic profile of some of the designed analogues was comparable to that of Topotecan, the FDA approved drug and better than the parent molecule Camptothecin. Keywords: ADME-T, cancer, camptothecin, topoisomerase I, in-silico designing, molecular docking, QSAR.