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设计和识别针对RET的新药候选药物:使用道元动力学准确估计药物亲和力

Karnati Ganesh Reddy¹, Atanu K Metya¹

¹Department of Chemical and Biochemical Engineering, Indian Institute of Technology Patna, Patna 801106, India.

International journal of biological macromolecules

|July 14, 2025

概括

新型阿尼利诺基纳氨酸衍生物对转移过程中重新排列 (RET) 受体氨酸激酶 (RTK) 和其突变具有强烈的抑制作用. 这些化合物克服药物耐药性,为向癌症治疗提供了一个有希望的途径.

科学领域:

生物化学和分子生物学
计算化学计算化学
药理学药理学是指药理学的学科.

背景情况:

在转移 (RET) 过程中重新排列的受体氨酸激酶 (RTK) 对细胞生长至关重要;突变驱动癌症.
由于RET-RTK突变导致药物耐药性,现有的向疗法面临限制.
了解耐药性机制和识别新型抑制剂对于有效的癌症治疗至关重要.

研究的目的:

设计新的anilinoquinazoline衍生物作为RET-RTK的潜在抑制剂.
评估这些衍生物与野生类型和突变RET蛋白质的结合亲和力和耐药性.
利用计算方法准确估计受体-连接体结合的自由能量.

主要方法:

利诺基纳林衍生物的设计和合成.
计算方法,包括漏斗-元动力学模拟,以估计结合的自由能量.
对野生类型和突变RET蛋白与参考药物vandetanib的结合 afinities 的比较.

主要成果:

与vandetanib相比,V2,V5和G5衍生物表现出较高的结合亲和力和对野生和突变RET蛋白的抗性.
道元动力学模拟结果为vandetanib与野生类型RET (-5.95 ± 2.1 kcal mol-1) 的绝对结合能量,与实验数据 (-8.75 kcal mol-1) 一致.
强大的衍生品V2与野生型RET (-7.2 ± 2.2 kcal mol-1) 呈现出强烈的结合亲和力.

结论:

利诺基纳林衍生物V2,V5和G5是RET-RTK的强有力的抑制剂,包括耐药形式.
衍生V2显示显著的承诺作为一个新的RET抑制剂用于向癌症治疗.
计算方法可以准确地预测结合亲缘关系,有助于开发下一代TK抑制剂.

关键词:

亚尼利诺基纳氨酸是什么?有约束力的自由能源.在RET基因酶突变中.

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