TARGETTING THE 3BGQ - PIM1 KINASE INTERACTION WITH A SERIES OF NOVEL DITHIOCARBAMATE SUBSTITUTED 2-OXOINDOLE DERIVATIVES- IN SILICO STUDIES

Abstract

Objective: Cancer is the major cause of mortality in most of the developing countries. Enormous chemotherapeutic agents developed are still need improvements in survival rates and quality of life for cancer patients. Pro-viral Integration site of Moloney murine leukemia virus (PIM1) is a family of serine/threonine kinase, regulated by calcium/calmudulin have been identified as a unique molecular target in oncogenesis. PIM1 has significant role in cell cycle regulation, cell survival, apoptosis, cellular senescence, drug resistance and it is emerging as a potential biomarker in number of human malignancies. Today many interesting PIM1 inhibitors are developed and few withdrawn from phase1 and 2 clinical trials, due to lack of bioavailability and toxicity. Hence the purpose of the present study is to develop more potent and less toxic compounds. Material and Method: A series of novel 2-oxindoles with dithiocarbamates were designed as PIM1 inhibitors. All molecules were subjected to Molsoft, Molinspiration, Swiss ADME and pkCSM to predict their molecular properties which are important for drug candidate. Further, in order to find the binding affinity of designed molecules with PIM1 kinase protein and to rationalize their anticancer activity, molecular docking study was performed. Result and Discussion: Results revealed that all designed compounds fulfilled the criteria for good oral bioavailability, low toxicity and the potential inhibitory activities. All of them were docked into active site of PIM1 kinase with AutoDock Vina software. In conclusion, according to the binding energy values, compound 16 and 24 showed equivalent dock score -9.7 kcal/mol which are comparable with previously reported compounds AZ1208 and SGI 1776. This finding will help the researchers in the design of a better drug for the treatment of cancer.