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混合虚拟查确定了二皮拉碳胺衍生物作为具有抗结核活性的新型直接InhA抑制剂

Auradee Punkvang¹, Bongkochawan Pakamwong², Naruedon Phusi²

¹Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand.

Biochimica et biophysica acta. General subjects

|May 28, 2025

概括

一种新的混合虚拟查方法确定了有前途的二皮拉碳胺衍生物作为结核病的潜在治疗方法. 这些化合物表现出抗菌活性和良好的安全性,为药物开发提供了新的希望.

科学领域:

药用化学医学化学
药物发现药物发现药物发现
计算化学的计算化学

背景情况:

直接抑制Mycobacterium tuberculosis enoyl-acyl载体蛋白减少酶 (M. tuberculosis InhA) 的药物对于对抗耐异酸结核病至关重要.
以前的基于结构的虚拟查产生了具有有限抗菌细菌活性 (MIC>100μg/mL) 的抑制剂.

研究的目的:

通过整合基于连接体和结构的虚拟查来增强强效的M.结核病InhA抑制剂的发现.
为了确定新的抗结核化合物,提高有效性和安全性.

主要方法:

采用了混合虚拟选策略,结合了基于连接体和结构的方法.
生物测试 (MIC,IC50) 用于验证抑制M.结核病生长和InhA活动的抑制剂疗效.
进行了分子动力学模拟,以了解化合物-蛋白质相互作用.

主要成果:

混合方法确定了14个匹配结果,其中二皮拉碳胺衍生物 (化合物3和10) 显示出显著的希望.
化合物3和10的MIC值分别为25和50微克/毫升,IC50值分别为10.60±0.56微米和5.08±0.30微米.
分子动力学模拟揭示了InhA结合口袋中的二皮拉碳胺部分与NAD+之间的关键结相互作用. 化合物3和10在高达100微克/毫升的Caco-2细胞中没有显示出毒性.

结论:

综合虚拟查策略成功识别了强大的二皮拉碳胺衍生物作为新型抗结核剂的化合物.
化合物3和10代表了进一步优化的有希望的起点,因为它们的抗菌活性,有利的安全性,以及与InhA目标的相互作用.
在测试中解决化合物沉对于未来的发展至关重要.

关键词:

这是一种InhA抑制剂.在M.结核病.分子动力学模拟模型结核病是一种疾病.虚拟选是一个虚拟的选.

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