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整合结构引导和基于碎片的抑制剂设计,以对抗抗达基林耐药的 Mycobacterium 结核病:一个分子动力学研究

Alankar Roy¹, Prantik Banerjee¹, Ishani Paul¹

¹Amity Institute of Biotechnology, Amity University, Kolkata, India.

Journal of biomolecular structure & dynamics

|December 23, 2024

概括

一种新的候选药物,L136,在耐药结核病菌株中有效抑制ATP合成酶. 它克服了抵抗机制,并显示出强大的安全性,为临床试验铺平了道路.

科学领域:

药物发现和开发药物发现和开发
分子生物学分子生物学
药用化学医学化学

背景情况:

贝达基林 (Bedaquiline,简称BDQ) 是一种FDA批准的药物,其向的是Mycobacterium tuberculosis中的ATP合成酶.
抗BDQ耐药性与心脏毒性和ATP合成酶c子单元 (ATPc) 中的突变有关.
由于耐药性和毒性,现有的疗法面临挑战.

研究的目的:

确定抑制ATPc活性的新型候选药物,以提高疗效和降低毒性.
为了研究ATPc抑制的结构功能关系.
克服现有的贝达基林抗药机制.

主要方法:

创建三个化合物库:重新使用的BDQ类似物,天然植物化合物和实验BDQ衍生物.
使用了分子动力学模拟,虚拟选,PCA,DCCM和结合亲和力分析.
评估了L136的结合性自由能量和pIC50值与野生类型和突变ATPc.

主要成果:

L136证明了野生类型和突变ATPc的强烈抑制,包括BDQ耐药变种.
L136诱导了ATPc的明显形状变化,有效地与c9旋转环结合.
L136表现出有利的ADMET配置文件,这表明毒性风险较低.
L136克服了ATPc突变中的疏水平台变化,这些突变阻碍了BDQ结合.

结论:

L136是治疗多抗药结核病 (MDR-TB) 的有希望的候选药物.
L136的作用机制与BDQ不同,有效抑制了耐药的ATPc变体.
L136需要在体内研究和未来的临床试验中进行进一步调查.

关键词:

这是ATP合成酶.多种药物耐药结核病.贝达奎林类似物在C-Ring中,使用C-Ring.碎片的替代碎片的替代自然植物产品天然植物产品

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