抗微生物和对其毒作用负责的标之间的相互作用:分子动力学模拟
Yury Lisnyak1, Artur Martynov1, Boris Farber1
1Department of Laboratory and Clinical Department of Molecular Immunopharmacology, Mechnikov Institute of Microbiology and Immunology of National Academy of Medical Sciences, Kharkov, Ukraine.
Current drug safety
|September 6, 2023
概括
通过减少其正电荷来修改多素B可以降低脏积累和毒性. 这项分子动力学研究揭示了用于开发更安全的抗耐药性感染的多胺衍生物的结构性见解.
科学领域:
- 药理学和毒理学 药理学和毒理学
- 计算化学计算化学
- 分子生物学分子生物学
背景情况:
- 聚胺抗生素对于治疗多药耐药的格拉姆阴性细菌至关重要.
- 聚米辛治疗受到显著毒性的限制,通常与通过巨结合的脏积累有关.
- 开发较少毒的多衍生物是传染病治疗的关键未满足需求.
研究的目的:
- 为了研究多素诱导的毒性在原子层面的结构基础.
- 阐明聚米辛B及其衍生品NAB7061与脏蛋白巨蛋白之间的相互作用机制.
- 为了指导合理设计具有减少毒性的多胺衍生物.
主要方法:
- 用分子动力学模拟来建模聚米辛B和NAB7061与巨的相互作用.
- 模拟使用了YASARA结构程序,在NPT组合条件下使用明确的水和离子.
- 使用AMBER03力场,以10 ns平衡,然后在298 K和pH 7.4.4下进行25 ns的生产阶段.
主要成果:
- 聚米辛B与美加林形成稳定的复合物,与已知的阴离子联体结合机制一致.
- 与NAB7061衍生品相比,美加林和聚米辛B之间的相互作用更强烈.
- 确定了结构上的差异,解释了NAB7061.1.的降低毒性.
结论:
- 对比分子动力学模拟揭示了像NAB7061.1.这样的多胺衍生物的较低毒性结构先决条件.
- 削弱聚米辛与美加林的结合亲和力是一种有前途的策略,可以预防聚米辛诱导的毒性.
- 这些发现支持有目的地开发更安全的多胺基抗生素.
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