Related Experiment Video
Updated: Aug 8, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study
Fanglin Liang1, Zhengzhong Kang2, Xianqiang Sun3
1Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China.
Abstract:
The mutant KRAS was considered as an "undruggable" target for decades, especially KRASG12D. It is a great challenge to develop the inhibitors for KRASG12D which lacks the thiol group for covalently binding ligands. The discovery of MRTX1133 solved the dilemma. Interestingly, MRTX1133 can bind to both the inactive and active states of KRASG12D. The binding mechanism of MRTX1133 with KRASG12D, especially how MRTX1133 could bind the active state KRASG12D without triggering the active function of KRASG12D, has not been fully understood. Here, we used a combination of all-atom molecular dynamics simulations and Markov state model (MSM) to understand the inhibition mechanism of MRTX1133 and its analogs. The stationary probabilities derived from MSM show that MRTX1133 and its analogs can stabilize the inactive or active states of KRASG12D into different conformations. More remarkably, by scrutinizing the conformational differences, MRTX1133 and its analogs were hydrogen bonded to Gly60 to stabilize the switch II region and left switch I region in a dynamically inactive conformation, thus achieving an inhibitory effect. Our simulation and analysis provide detailed inhibition mechanism of KRASG12D induced by MRTX1133 and its analogs. This study will provide guidance for future design of novel small molecule inhibitors of KRASG12D.
Insights
The KRAS G12D protein, once undruggable, can now be targeted by MRTX1133. This inhibitor stabilizes KRAS G12D in inactive states by binding to Gly60, offering new hope for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- The KRAS G12D mutation is a key driver in many cancers and has historically been considered an
- undruggable
- target due to its structure.
- Developing inhibitors for KRAS G12D is challenging because it lacks a thiol group for covalent binding.
Purpose of the Study:
- To elucidate the molecular mechanism by which MRTX1133 and its analogs inhibit KRAS G12D.
- To understand how MRTX1133 binds to both active and inactive states of KRAS G12D without activating it.
- To provide insights for the design of novel KRAS G12D inhibitors.
Main Methods:
- All-atom molecular dynamics (MD) simulations.
- Markov state modeling (MSM) to analyze protein dynamics and binding mechanisms.
- Conformational analysis and hydrogen bonding interactions.
Main Results:
- MRTX1133 and analogs were found to stabilize KRAS G12D in distinct inactive or active conformations.
- The compounds form hydrogen bonds with Gly60, stabilizing the switch II and switch I regions in a dynamically inactive conformation.
- This interaction effectively inhibits the oncogenic function of KRAS G12D.
Conclusions:
- MRTX1133 and its analogs inhibit KRAS G12D by stabilizing it in inactive conformations through specific hydrogen bonding interactions.
- The findings offer a detailed understanding of the inhibition mechanism, guiding future development of targeted cancer therapies.
- This research paves the way for designing new small molecule inhibitors against KRAS G12D-driven cancers.
More Related Videos
15:05Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016