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通过结合分子动力学模拟和社区网络分析,阐明点突变对FGFR3抑制剂耐药性的潜在影响

Bo Liu^1,2,3, Juntao Ding^1,2,3, Yugang Liu^1,3

¹The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.

Journal of computer-aided molecular design

|June 3, 2023

概括

FGFR3突变降低了对FGFR3激酶的药物亲和力,导致对泛FGFR抑制剂的耐药性. 分子动力学模拟揭示了涉及链区域和A环变化的机制,指导了新的抑制剂开发.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

纤维细胞生长因子受体3 (FGFR3) 激酶突变与各种癌症有关.
开发有效的FGFR3突变激酶抑制剂至关重要,但耐药性机制尚不清楚.

研究的目的:

阐明在存在FGFR3突变时对泛FGFR抑制剂产生抗性的分子机制.
为设计新型FGFR3突变激酶抑制剂提供理论基础.

主要方法:

利用分子动力学 (MD) 模拟进行全球和本地分析.
雇佣了具有约束力的免费能源计算,雨抽样和社区网络分析.

主要成果:

已经证明FGFR3突变可以降低抑制剂和FGFR3激酶之间的结合亲和力.
确定了潜在的抗性机制,包括链区域残留环境的变化和A环对全网络的干扰.

结论:

使用MD模拟系统地阐明了由FGFR3突变驱动的泛FGFR抑制剂耐药性的机制.
这些发现为开发下一代FGFR3突变激酶抑制剂提供了理论指导.

关键词:

所有的通讯网络都是单一的通信网络.药物耐药性药物耐药性药物耐药性在FGFR3中.模拟MDMD的模拟雨采样是统一的采样方式.

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