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.

FGFR3激酶突变与多种恶性肿瘤相关，但FGFR3突变抑制剂的研究很少。此外，激酶结构域突变引起泛FGFR抑制剂耐药的机制仍不清楚。在本研究中，我们试图通过基于分子动力学模拟、结合自由能分析、伞形抽样和群落网络分析的全局分析和局部分析来解释FGFR3突变的耐药机制。结果显示，FGFR3突变导致药物与FGFR3激酶之间的亲和力降低，这与报道的实验结果一致。可能的机制是突变通过改变蛋白质与药物结合的铰链区附近的残基环境，或者通过影响 A 环并干扰变构通讯网络来影响药物-蛋白质亲和力。总之，我们基于分子动力学模拟策略，系统阐明了FGFR3突变引起的泛FGFR抑制剂耐药的潜在机制，为FGFR3突变激酶抑制剂的开发提供了理论指导。