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Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61
1Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus UPC, Barcelona, 08034, Catalonia, Spain.
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.
Insights
NRAS-mutant melanoma is aggressive, lacking targeted therapies. This study reveals NRAS Q61 mutation effects on protein structure, identifying new pockets for drug design and a prototype inhibitor HM-387 for NRAS-Q61R.
Area of Science:
- Oncogenic signaling pathways
- Molecular dynamics simulations
- Drug discovery
Background:
- NRAS-mutant melanoma is a deadly cancer subtype with poor survival rates.
- Over 40 years have passed without a clinically approved therapeutic agent directly targeting NRAS mutations.
- Understanding NRAS conformational changes is crucial for developing effective treatments.
Purpose of the Study:
- To elucidate the atomic-level conformational effects of NRAS Q61 mutations.
- To identify novel, targetable pockets in NRAS mutants for therapeutic intervention.
- To develop an in silico method for designing potential oncogene inhibitor prototypes.
Main Methods:
- Microsecond-scale molecular dynamics simulations of NRAS Q61 mutants.
- Identification of specific allosteric pockets in GTP-bound NRAS-Q61R, NRAS-Q61K, and NRAS-Q61L.
- Development of a novel isomer-sourced structure iteration method for in silico drug design.
Main Results:
- NRAS-Q61R and NRAS-Q61K mutations reveal a targetable pocket between Switch-II and alpha-helix 3.
- The NRAS-Q61L mutation presents a distinct targetable pocket.
- A designed prototype inhibitor, HM-387, was shown to target activated NRAS-Q61R.
- HM-387 can induce a transition of NRAS-Q61R to an inactive state.
Conclusions:
- Specific Q61 mutations in NRAS create unique druggable pockets.
- The developed in silico method facilitates the design of targeted oncogene inhibitors.
- The prototype HM-387 shows promise for targeting NRAS-Q61R in melanoma treatment.
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