通过高通量计算筛选,确定潜在的抗细菌乙酰黄嘌呤抗性蛋白 B (AcrB) 外排泵的药物。

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sanket Rathod, Sreenath Dey, Prafulla Choudhari, Deepak Mahuli, Sneha Rochlani, Rakesh Dhavale, Somdatta Chaudhari, Yasinalli Tamboli, Jaydeo Kilbile, Eerappa Rajakumara
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引用次数: 0

摘要

抗生素耐药性是一项紧迫的全球健康挑战,其部分原因是革兰氏阴性细菌中 AcrB(乙酰黄嘌呤抗性蛋白 B)蛋白的外排泵具有显著的外排能力。在这项研究中,我们采用了一种多途径计算筛选策略,包括分子对接、In silico 吸收、分布、代谢、排泄和毒性(ADMET)分析、药物亲和性评估、分子动力学模拟和密度泛函理论研究,以确定能够对抗 AcrB 介导的抗生素耐药性的新药。配体库取自 COCONUT 数据库。计算分析揭示了四个有希望的命中分子(CNP0298667、CNP0399927、CNP0321542 和 CNP0269513)。值得注意的是,CNP0298667 表现出最高的负结合亲和力(-11.5 kcal/mol),表明其具有破坏 AcrB 功能的强大潜力。重要的是,所有四个新发现都符合严格的药物亲和性标准,并显示出良好的硅学 ADMET 特征,突显了其进一步开发的潜力。超过 100 ns 的 MD 模拟显示,CNP0321542-4DX5 和 CNP0269513-4DX5 复合物与 AcrB 外排泵形成了强大而稳定的相互作用。这些发现的新药为设计和优化新型疗法提供了一个很好的起点,这些疗法旨在消除革兰氏阴性细菌中由 AcrB 介导的抗生素耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
High-throughput computational screening for identification of potential hits against bacterial Acriflavine resistance protein B (AcrB) efflux pump.

Antibiotic resistance is a pressing global health challenge, driven in part by the remarkable efflux capabilities of efflux pump in AcrB (Acriflavine Resistance Protein B) protein in Gram-negative bacteria. In this study, a multi-approached computational screening strategy encompassing molecular docking, In silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis, druglikeness assessment, molecular dynamics simulations and density functional theory studies was employed to identify novel hits capable of acting against AcrB-mediated antibiotic resistance. Ligand library was acquired from the COCONUT database. Performed computational analyses unveiled four promising hit molecules (CNP0298667, CNP0399927, CNP0321542 and CNP0269513). Notably, CNP0298667 exhibited the highest negative binding affinity of -11.5 kcal/mol, indicating a possibility of strong potential to disrupt AcrB function. Importantly, all four hits met stringent druglikeness criteria and demonstrated favorable in silico ADMET profiles, underscoring their potential for further development. MD simulations over 100 ns revealed that the CNP0321542-4DX5 and CNP0269513-4DX5 complexes formed robust and stable interactions with the AcrB efflux pump. The identified hits represent a promising starting point for the design and optimization of novel therapeutics aimed at combating AcrB-mediated antibiotic resistance in Gram-negative bacteria.

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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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