基于药理的方法鉴定伤寒沙门氏菌 LpxC 酶的强效抑制剂

IF 3.8 Q2 CHEMISTRY, PHYSICAL Chemical Physics Impact Pub Date : 2024-09-10 DOI:10.1016/j.chphi.2024.100729
Mohammad Z. Ahmed , Ali S. Alqahtani , Prakash kumar Shukla , Sanjit Kumar , Sudhir Kumar Pal
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引用次数: 0

摘要

抗菌药耐药性(AMR)是目前全球关注的健康问题,主要由细菌、病毒、寄生虫和真菌等微生物对抗菌药产生耐药性引起。沙门氏菌可引起多种疾病,但主要是伤寒。最令人担忧的是,该菌种的非伤寒菌株和伤寒菌株的抗药性都在上升。为解决这一问题,有必要确定开发新型抗菌药物的新目标和新策略。脂质 A 是一种能调节人体免疫系统的强细菌内毒素,是沙门氏菌感染过程中产生的毒力因子的关键组成部分。革兰氏阴性菌通过九种酶的级联途径合成脂质 A。脂质 A 生物合成的第二步由 LpxC 催化,LpxC 是一种 Zn+ 依赖性金属酰胺酶,被认为是限制速率的一步。在本手稿中,我们利用蛋白质-配体相互作用指纹(PLIF)衍生的药效模型来筛选针对伤寒沙门氏菌 LpxC(StLpxC)的小分子(锌数据库天然产物库、Asinex 数据库、噻吩类似物)。我们还对命中率最高的分子进行了 MD 模拟和 ADMET 研究。我们确定了三个最佳化合物:s1_dl_mseq2、s1_ll_mseq2 和 s2_ll_mseq8,它们与 LpxC 活性位点的结合亲和力很强。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Pharmacophore-based approach for the identification of potent inhibitors against LpxC Enzyme from Salmonella Typhi

Antimicrobial resistance (AMR) is currently a global health concern, mostly caused by microorganisms like bacteria, viruses, parasites, and fungi that acquire resistance to antimicrobial drugs. Salmonella is responsible for a variety of diseases but mainly cause typhoid. The primary concern is the rise in resistance in both non-typhoid and typhoid strains of this species. To address this issue, it is necessary to identify novel targets and strategies for the development of new antibacterial drugs. Lipid A, a strong bacterial endotoxin that modulates the immune system in human, is a key component of the virulence factor generated during the salmonella infection. Lipid A is synthesized in case of Gram-negative bacteria by cascade of nine enzyme pathway. The second step in case of Lipid A biosynthesis, catalysed by LpxC, a Zn+ dependent metallo-amidase considered as rate limiting step. In this manuscript we have used protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models to screen small molecules (natural products library from Zinc database, Asinex database, Thiophene analogues) against Salmonella typhi LpxC (StLpxC). Further top hit molecules were subjected to MD-simulation and ADMET studies. We identified three optimal compounds, s1_dl_mseq2, s1_ll_mseq2, and s2_ll_mseq8, that exhibit strong binding affinity towards the LpxC active site.

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来源期刊
Chemical Physics Impact
Chemical Physics Impact Materials Science-Materials Science (miscellaneous)
CiteScore
2.60
自引率
0.00%
发文量
65
审稿时长
46 days
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