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Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study

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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.

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Data availability

Data are freely available upon request of the corresponding author.

Abbreviations

KRAS:

Kirsten rat sarcoma virus oncogene

GDP:

Guanosine diphosphate

GTP:

Guanosine triphosphate

GppNHp:

Guanosine 5′-(β-γ-imido) triphosphate

RMSD:

Root mean squared deviation

MD:

Molecular dynamics

TIP3P:

Transferable interatomic potential with three points

MSM:

Markov state model

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Acknowledgements

F.L. would like to thank Zhenchao Wei for his help with the analysis script.

Funding

This work was supported by the National Natural Science Foundation of China (Grant 22063004), the Youth project of Jiangxi Provincial Department of Education (Grant GJJ170696), the University Doctoral Fund (Grant 2017BSQD016), the Open Fund of Provincial Research Platform (Grant KFGJ19014), and the horizontal research funding (Grant H20210713181758000003).

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Authors and Affiliations

  1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China

    Fanglin Liang, Xuemin Duan & Jianxin Cheng

  2. AutoDrug Biotech Co. Ltd, Aly. 795 KangWei Rd., Pudong New Area, Shanghai, China

    Zhengzhong Kang & Xianqiang Sun

  3. Synrx Therapeutics (Hanghzou) CO. Ltd, ROOM 201, Building 4, Lane 1309, CangQian Rd., Yuhang Area, Hangzhou, China

    Hu He

  4. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China

    Jiao Chen

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  1. Fanglin Liang
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  2. Zhengzhong Kang
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  3. Xianqiang Sun
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  4. Jiao Chen
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  5. Xuemin Duan
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  6. Hu He
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Contributions

FL carried out the molecular dynamics simulations. FL and XS designed the study and analyzed the data. JC was responsible for the project. FL, XS, ZK, XD, HH, and JC contributed to writing and commenting on the manuscript.

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Correspondence to Xianqiang Sun, Hu He or Jianxin Cheng.

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Liang, F., Kang, Z., Sun, X. et al. Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study. J Comput Aided Mol Des 37, 157–166 (2023). https://doi.org/10.1007/s10822-023-00498-1

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