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Molecular Dynamics simulation of NRAS-Q61 oncogenes and new strategies for in silico drug design

Hu, Z.; Marti, J.

2023-05-26 cancer biology
10.1101/2023.05.25.542304 bioRxiv
Show abstract

The NRAS-mutant subset of melanoma represents the most aggressive and the deadliest types associated with poorer overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations have been clinically approved yet. Herein, based on microsecond scale molecular dynamics simulations, the concept of NRAS-Q61 mutation classification was firstly proposed. NRAS Q61 positively charged mutations (Q61R and Q61K) was classified together, with a specific targetable pocket, while NRAS-Q61L classified into another category. Moreover, the isomer-sourced structure iteration (ISSI) method was developed for the in silico design of potential inhibitors (HM-516) targeting NRAS mutations. Overall, through this article, we hope to provide the academic and clinical community with new perspective and understanding of NRAS oncoproteins, and propose possible solution to this challenge.

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