LAUSR

KRAS mutation is prevalent in around 30% of all cancers and is an undruggable molecular target. Of seven mutations at codon 12 and 13, only one, the G12C mutant is finally proven to be druggable, as evidenced by the recent USFDA approval of sotorasib. Investigation of other small molecules targeting G12C and G12D are undergoing clinical trials. Understanding the fine structural details is a prerequisite to design specific inhibitors which also requires in depth molecular exploration. We used bioinformatics as a tool to analyze the KRAS protein's GTP (guanosine triphosphate) binding dynamics when mutated. KRAS undergoes significant conformational changes, affecting GTP binding conformation within the active site pocket of KRAS due to high torsional strains, hydrophobicity, and altered Switch I and II regions. GTP molecule for wildtype had a low torsional strain of 10.71, and is the only molecule, in comparison to KRAS mutant bound GTP, to have a glycine at position 10 interacting with its nitrogenous base. All mutant KRAS proteins lacked the interaction of glycine with the nitrogenous base. The binding affinity of wildtype (WT) KRAS for the gamma-phosphate was lower in scoring compared to the mutated KRAS protein in multiple analyses. This study provides an insight to the GTP-KRAS protein binding details that are important to define parameters required to be explored to design the appropriate inhibitor for each different type of mutant KRAS protein.