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通过综合虚拟查和分子动态模拟来发现强效的CSK抑制剂

Roufen Chen^1,2, Yuchen Wang², Zheyuan Shen²

¹Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.

Archiv der Pharmazie

|May 29, 2024

概括

研究人员发现了一种新型化合物,可以强烈抑制C-终端Src激酶 (CSK),这是三阴性乳腺癌 (TNBC) 的关键驱动因素. 这一发现为TNBC治疗提供了一个有前途的新疗法途径.

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:

过度表达/激活C终端Src激酶 (CSK) 与三阴性乳腺癌 (TNBC) 的进展有关,导致瘤发作,生长,转移和耐药性.
向CSK为新型TNBC治疗提供了一个有希望的战略,但有效的抑制剂很少.

研究的目的:

确定和描述C端Src激酶 (CSK) 的新型抑制剂,用于潜在的三阴性乳腺癌 (TNBC) 治疗.
为了验证新发现的CSK抑制剂的疗效和作用机制.

主要方法:

采用了全面的虚拟选协议,集成基于能源的方法,人工智能驱动的评分 (Attentive FP),滑动对接和MM / GBSA进行严格的复制.
利用同质的时间解析光 (HTRF) 生物测试来确定抑制活性 (IC50).
评估化合物在抑制TNBC细胞系 (MDA-MB-231,Hs578T,SUM159) 的增殖中的有效性,并分析细胞周期和细胞亡.
进行了分子动力学模拟,以阐明化合物和CSK之间的结合相互作用.

主要成果:

发现了一种强大的CSK抑制剂,IC50为1.6nM.
鉴定的分子 (分子2) 在多个TNBC细胞系中显示出显著的生长抑制,与达沙替尼比可比.
用分子2治疗诱导了G1阶段细胞循环停止和促进了细胞亡.
分子动力学模拟提供了关于该化合物的与CSK的结合相互作用的见解.

结论:

这种新型的CSK抑制剂对TNBC细胞表现出强大的抗癌活性.
这种化合物代表了开发针对三阴性乳腺癌的向疗法的一个有希望的领先地位.
对其机制和治疗潜力的进一步研究是有必要的.

关键词:

在 CSK CSK 的位置上.在MM/GBSA中使用.一个专心的FP.三重阴性乳腺癌是什么?虚拟选虚拟选虚拟选

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