KRAS is a frequently mutated oncogene in human cancer cells. While many attempts to target this oncoprotein have been largely unsuccessful, recent technological advances in drug discovery and design have renewed the aspiration to develop a direct KRAS inhibitor. The focus of this study is to elucidate structural transformations of KRAS induced by the oncogenic A146 mutations, which are known to appear in several cancers including colorectal cancer and in some forms of leukemia. Previous experimental studies have revealed reduced affinity of the nucleotides for the mutated KRAS proteins, suggesting that they may be more attractive drug targets than the wild type protein. We have conducted a series of molecular simulation studies to elucidate the conformational changes that occur in the nucleotide binding pocket of the A146 mutants. Such structural insight will then serve as a basis for the design of potent small molecule inhibitors directly interacting with the nucleotide binding site.

Structural insight into KRAS A146 mutations from molecular simulations

253rd National Meeting (2017)

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