Establishing the mutational effect on the binding susceptibility of AMG510 to KRAS switch II binding pocket: Computational insights

Abstract

After decades of leaving patients with limited treatment options due to the ‘undruggability’ of Kirsten rat sarcoma, the kernel was finally cracked with the discovery of Sotorasib. This novel drug binds to a small pocket on the switch II of Kirsten rat sarcoma by exploiting the mutation that occurs at codon 12 wherein glycine is replaced by cysteine. However, this pocket is not only prone to cysteine mutation but other mutations occur as well including at codon 13. These mutations have been reported to drive cancer in the lungs, colorectal and in solid tumors with varying degree of expressions. Sotorasib is therefore only effective in a small group of patients especially those expressing cysteine at codon 12, reminding drug hunters of the unfinished work. This study employs computational techniques to understand the susceptibility of the mutated binding pocket to the binding of Sotorasib. It was revealed that the binding affinity of Sotorasib to other mutations aside Cysteine was significantly affected via the total free binding energies presented by the mutated complexes. Furthermore, the quantum of energy contributed by the mutated residues except cysteine was significantly reduced suggesting the binding of Sotorasib is enhanced in only cysteine mutated Kirsten rat sarcoma. Residual interaction network showed Sotorasib in complex with the cysteine mutated protein presented the highest degree centrality, shortest path betweenness, shortest path centrality and shortest path degree indicating Sotorasib controls more information flow within the cysteine mutated protein than in other mutations. Insight unraveled here will provide aid in the development of pan Kirsten rat sarcoma inhibitory small molecules.