Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state

Abstract

The NRAS-mutant subset of melanoma represent some of the most aggressive and deadliest types associated with poor overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations has been clinically approved. In this work, based on microsecond scale molecular dynamics simulations, the effect of Q61 mutations on NRAS conformational characteristics is revealed at the atomic level. The GTP-bound NRAS-Q61R and Q61K mutations show a specific targetable pocket between Switch-II and α-helix 3 whereas the NRAS-Q61L non-polar mutation category shows a different targetable pocket. Moreover, a new isomer-sourced structure iteration method has been developed for the in silico design of potential inhibitor prototypes for oncogenes. We show the possibility of a designed prototype HM-387 to target activated NRAS-Q61R and that it can gradually induce the transition from the activated NRAS-Q61R to an “off-like” state.