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针对循环林依赖性激酶9的强效抑制剂通过虚拟高通量选和绝对结合的自由能量计算被发现

Shipeng Wang¹, Fengjiao Liu¹, Pengfei Li²

¹School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China. fjliu@sues.edu.cn.

Physical chemistry chemical physics : PCCP

|January 25, 2024

概括

研究人员使用虚拟查和分子动力学发现了用于癌症治疗的新型环素依赖激酶9 (CDK9) 抑制剂. 提高分子刚性提高了结合亲和力,提供了一个有前途的新治疗策略.

科学领域:

生物化学生物化学
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:

循环素依赖性激酶9 (CDK9) 是mRNA转录的关键调节者.
用激酶抑制剂向CDK9是癌症治疗的潜在治疗策略.

研究的目的:

通过基于结构的虚拟查方法发现新的CDK9抑制剂.
通过先进的计算方法优化抑制剂结合模式和亲和力.

主要方法:

在ZINC15数据库中进行虚拟高通量选,以识别潜在的激酶抑制剂.
分子动力学模拟以改进预测的结合姿势.
绝对具有约束力的自由能量计算,使用自由能量扰动方案来估计约束亲和关系.

主要成果:

识别潜在的新型CDK9抑制剂.
分子动力学揭示了重要的结合模式变化,这对于准确的亲和力预测至关重要.
结构修改,包括形成环来增强刚性,通过减少损失成功增加了结合亲和力.

结论:

这项研究成功地确定并优化了新的CDK9抑制剂.
分子动力学模拟对于准确预测结合姿势和亲和关系至关重要.
通过结构修改增强分子刚性是一种有效的策略,可以提高对CDK9的抑制剂结合亲和力,从而支持其作为癌症治疗药物的发展.

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