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用绝对结合的自由能量模拟来识别表皮生长因子受体氨酸激酶的新型抑制剂

Huaxin Zhou¹, Haohao Fu¹, Xueguang Shao¹

¹Research Center for Analytical Sciences, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China; Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, China.

International journal of biological macromolecules

|February 14, 2025

概括

针对三重突变表皮生长因子受体 (EGFRTM) 的新型抑制剂显示出优异的结合亲和力. 这些新候选药物为克服C797S介导的耐药性在非小细胞肺癌治疗中提供了一个有希望的策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

表皮生长因子受体 (EGFR) 激酶域的突变,包括C797S突变,导致对向疗法的耐药性.
三重突变EGFR (L858R/T790M/C797S,EGFRTM) 在非小细胞肺癌 (NSCLC) 治疗中提出了重大挑战.
开发有效对抗耐药EGFR突变的新型抑制剂对于改善患者的治疗结果至关重要.

研究的目的:

确定和描述针对EGFRTM三重突变的新型抑制剂.
调查新的抑制剂候选者的结合相互作用和疗效.
探索克服EGFR突变NSCLC中C797S介导的耐药性的策略.

主要方法:

基于功能组的选,用于包含硫基和皮佩里迪尼尔基的抑制剂.
计算严格的绝对结合的自由能量计算.
自由能量分解分析以阐明关键的结合相互作用.

主要成果:

确定了一种类别中最好的抑制剂候选剂,其对EGFRTM的结合亲和力为-15.8 kcal/mol,优于目前的标准BLU-945 (-12.6 kcal/mol).
顶级候选人证明了与关键残留物K745,D800和R841.1的增强相互作用.
特别的相互作用,包括与K745的键和-π相互作用,被强调为对疗效至关重要的.

结论:

针对EGFRTM的新型抑制剂,特别是那些涉及氨酸残留物的新型抑制剂,显示出克服C797S介导耐药性的前景.
这些发现表明,对于具有抗性EGFR突变的NSCLC患者,有新的治疗策略.
开发的抑制剂代表了高级NSCLC治疗的潜在候选药物.

关键词:

绝对有约束力的自由能量模拟.分子动力学分子动力学虚拟选是一个虚拟的选.

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