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Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics
Bo Liu1,2,3, Juntao Ding1,2,3, Yugang Liu1,3
1The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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.
Insights
FGFR3 mutations decrease drug affinity for FGFR3 kinase, causing resistance to pan-FGFR inhibitors. Molecular dynamics simulations revealed mechanisms involving hinge region and A-loop alterations, guiding new inhibitor development.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Fibroblast Growth Factor Receptor 3 (FGFR3) kinase mutations are implicated in various cancers.
- Developing effective inhibitors for FGFR3 mutant kinases is crucial, yet resistance mechanisms remain poorly understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying resistance to pan-FGFR inhibitors in the presence of FGFR3 mutations.
- To provide a theoretical basis for designing novel FGFR3 mutant kinase inhibitors.
Main Methods:
- Utilized molecular dynamics (MD) simulations for global and local analyses.
- Employed binding free energy calculations, umbrella sampling, and community network analysis.
Main Results:
- FGFR3 mutations were shown to reduce the binding affinity between inhibitors and FGFR3 kinase.
- Identified potential resistance mechanisms including alterations in hinge region residue environment and A-loop interference with allosteric networks.
Conclusions:
- Systematically elucidated the mechanism of pan-FGFR inhibitor resistance driven by FGFR3 mutations using MD simulations.
- Findings offer theoretical guidance for the development of next-generation FGFR3 mutant kinase inhibitors.
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