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  3. Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis

Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis

  • J Comput Aided Mol Des. 2023 Jul;37(7):325-338. doi: 10.1007/s10822-023-00510-8.
Bo Liu 1 2 3,  Juntao Ding 1 2 3,  Yugang Liu 1 3,  Jianzhang Wu 2 3 4,  Xiaoping Wu 5 6,  Qian Chen 7,  Wulan Li 8 9 10
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China.
  • 3 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 4 The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, China.
  • 5 Institute of Tissue Transplantation and Immunology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
  • 6 MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China.
  • 7 Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314102, China. chenqian200709@163.com.
  • 8 The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. lwlwzmu@163.com.
  • 9 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China. lwlwzmu@163.com.
  • 10 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. lwlwzmu@163.com.
PMID: 37269435 DOI: 10.1007/s10822-023-00510-8
Abstract

FGFR3 kinase mutations are associated with a variety of malignancies, but FGFR3 mutant inhibitors have rarely been studied. Furthermore, the mechanism of pan-FGFR inhibitors resistance caused by kinase domain mutations is still unclear. In this study, we try to explain the mechanism of drug resistance to FGFR3 mutation through global analysis and local analysis based on molecular dynamics simulation, binding free energy analysis, umbrella sampling and community network analysis. The results showed that FGFR3 mutations caused a decrease in the affinity between drugs and FGFR3 kinase, which was consistent with the reported experimental results. Possible mechanisms are that mutations affect drug-protein affinity by altering the environment of residues near the hinge region where the protein binds to the drug, or by affecting the A-loop and interfering with the allosteric communication networks. In conclusion, we systematically elucidated the underlying mechanism of pan-FGFR inhibitor resistance caused by FGFR3 mutation based on molecular dynamics simulation strategy, which provided theoretical guidance for the development of FGFR3 mutant kinase inhibitors.

Keywords

Allosteric communication network; Drug resistance; FGFR3; MD simulations; Umbrella sampling.

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