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虚拟查和小分子抑制剂的多阶段计算分析向 Clostridioides difficile B 毒素

Runze Wang^1,2, Qiuyu Zhang¹, Yi Lin¹

¹Hangzhou Medical College, School of Laboratory Medicine and Bioengineering, Hangzhou, Zhejiang CN 310053, China.

Journal of medicinal chemistry

|October 1, 2025

概括

一种重新设计的药物Dirlotapide通过阻断其受体结合接口,有效地抑制Clostridioides difficile毒素B (TcdB). 这种泛亚型抑制剂在临床前模型中显示出治疗C. difficile感染 (CDI) 的前景.

科学领域:

微生物学微生物学
药理学药理学是指药理学的学科.
计算生物学计算生物学

背景情况:

艰难菌感染 (CDI) 是与抗生素相关的腹的主要原因.
毒素B (TcdB) 是CDI中的关键毒性因子,具有多种不同的受体结合接口 (RBI).

研究的目的:

以计算方式识别和重新使用FDA批准的药物作为TcdB的宽谱抑制剂.
为潜在的CDI治疗开发一个泛RBI,泛亚型TcdB抑制剂.

主要方法:

多阶段的计算管道包括虚拟选,分子对接,结合自由能量计算和分子动力学模拟.
使用表面等离子体共振 (SPR),循环二元化 (CD),体外基于细胞的试验和体外小鼠模型进行实验验证.

主要成果:

迪洛塔皮德被确定为一种化合物,具有与TcdB的高亲和度结合.
迪洛塔皮德保护Caco-2细胞免受TcdB诱导的细胞毒性,并在CDI的小鼠模型中证明有效.
临床前验证证实了肠道受限的药理动力学,低毒性和转化潜力.

结论:

迪洛塔皮德是一种有前途的,迅速重新定位的治疗剂,用于对抗临床相关的TcdB亚型.
这项研究突出了针对传染病的计算药物重新定位的潜力.

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