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用于识别新的Bcl-2抑制剂的药物再利用:体外,STD-NMR,分子对接和动态模拟研究

Noor Rahman¹, Humaira Zafar², Atia-Tul-Wahab²

¹H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.

|October 20, 2023

概括

这项研究重新定位了FDA批准的药物,以找到用于癌症治疗的新型Bcl-2抑制剂. 帕洛西丁HCl,卡维迪醇,克洛米胺HCl和克洛米芬酸盐显示出显著的抗增殖活性和Bcl-2蛋白相互作用.

科学领域:

在瘤学瘤学.
药理学药理学是指药理学的学科.
生物物理学的生物物理.

背景情况:

抗亡蛋白B细胞淋巴瘤2 (Bcl-2) 的过度表达有助于癌细胞抵抗化疗.
准Bcl-2是开发新型抗癌药物的关键策略.

研究的目的:

使用药物重定位方法系统地选FDA批准的药物用于BCL-2抑制.
评估已识别的化合物的体外抗癌活性和诱导亡的潜力.
使用生物物理和in-silico方法阐明候选药物和BCL-2之间的联结蛋白相互作用.

主要方法:

在实验室中,对HL-60癌细胞系进行了抗癌活性试验和亡试验.
选择的化合物经过和转移差核磁共振 (STD-NMR) 谱学.
用分子对接和分子动态模拟来分析药物-Bcl-2相互作用.

主要成果:

七十五种FDA批准的药物被选;帕罗克塞HCl,卡维迪洛,克洛米普拉HCl和克洛米芬酸盐对HL-60细胞表现出显著的抗增殖活性.
这些药物与参考药物venetoclax的IC50值相似,并在癌细胞中诱导了亡.
STD-NMR,对接和分子动力学模拟证实了这些药物与Bcl-2蛋白之间的相互作用,主要是通过疏水接触.

结论:

帕洛西丁HCl,卡维迪醇,克洛米胺HCl和克洛米芬酸盐被确定为强大的BCL-2抑制剂.
这些重新定位的药物需要进一步进行临床前和临床研究,作为潜在的抗癌剂.

关键词:

这是一种BCL-2蛋白质.卡尔维迪醇是一种克洛米芬是一种克洛米普拉胺是一种药物重新定位是药物重新定位.帕洛克西丁 (paroxetine) 是一种药物.在STD-NMR中.

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