Design of Inhibitors Against Kirsten Rat Sarcoma K RAS Protein

Abstract

Introduction: Cancer, a major health concern, is defined as an unusual growth of cells caused by numerous changes in gene expression leading to a dysregulated balance of cell proliferation and cell death. Mutations in Kirsten Rat Sarcoma (K-Ras) protein (a member of the Ras family, which belongs to the small GTPase super family) have often played a critical role in the development of cancer (particularly lung, colorectal, and pancreatic cancer). It regulates various physiological functions such as cell differentiation, proliferation, and apoptosis by acting as a molecular switch. Cell signaling turns off when Ras proteins bind to GDP (guanine diphosphate), and turns on when bind to GTP (guanine triphosphate). newline newlineThus, K-Ras protein plays a major role in controlling cell proliferation. Therefore, mutant K-Ras protein causes the cells to proliferate continuously due to dysregulation of Rasmediated signaling pathways. K-Ras mutation has been observed in more than 30% of almost all types of human cancer. The development of small molecule inhibitors against KRas has been a challenging task. Despite extensive research, the detailed mechanism of Ras with its adapter proteins is not fully understood. The main goal of the study is to understand the structure-function relationship of K-Ras protein and its mutants through molecular dynamics approach and community network analysis. This understanding would be translated into the design of small molecule inhibitors against K-Ras protein using structurebased and ligand-based drug-design approach (SBDD and LBDD). newlineMethods: Molecular dynamics (MD) simulation was performed for various bound and unbound form of K-Ras protein. The community network and suboptimal path analysis were performed to understand the regulation mechanism of nucleotide exchange at the catalytic site through the allosteric site of SOS protein. The information from experimental mutational studies was used to understand the impact of oncogenic mutants on it.