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针对CDK9 / 环素T1蛋白质-蛋白质相互作用的受抑制剂的结构导向设计和克隆

Mohammad Sadegh Taghizadeh¹, Mohsen Taherishirazi¹, Ali Niazi¹

¹Institute of Biotechnology, Shiraz University, Shiraz, Iran.

Frontiers in pharmacology

|May 29, 2024

概括

研究人员设计了突变来抑制循环素依赖性激酶9 (CDK9),这是癌症等疾病的关键参与者. 三种 (mp3,mp20,mp29) 显示与CDK9结合的高亲和力,提供潜在的治疗策略.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

循环素依赖性激酶9 (CDK9) 与各种病理有关,包括HIV-1感染和癌症.
CDK9-cyclin T1相互作用对CDK9的活性至关重要,使其成为一个可行的治疗点.
抑制这种蛋白质-蛋白质相互作用是针对CDK9的向疗法的有希望的策略.

研究的目的:

设计和描述针对CDK9.9的环林T1结合区域的突变.
确定具有高亲和力和低结合能的新型抑制剂,用于CDK9.
探索这些的重组生产的潜力.

主要方法:

使用 Osprey 软件对 7776 种突变的计算设计.
对CDK9.9的结亲和力和自由结合能的in silico分析.
评估的安全概况和动态行为.
在大肠杆菌中进行重组表达的结构的设计.

主要成果:

三种 (mp3,mp20,mp29) 被确定为强大的CDK9抑制剂.
这些具有较高的结合亲和力和较低的自由结合能量对CDK9.
mp3和mp29与CDK9.9中的保存序列 (残留60-66) 相互作用.
设计的体显示出有利的预测安全性和可溶性,可用于重组生产.

结论:

设计的体代表有希望的化合物,可以抑制CDK9-环素T1复合体.
这些具有作为治疗CDK9相关疾病的治疗剂的潜力.
需要进一步的实验验证,以确认治疗开发的生物活性和选择性.

关键词:

这就是MMPBSA.发现药物的发现.分子对接的分子对接.分子动力学模拟模拟突变发生的突变发生.这是一种抑制剂.

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