通过计算设计,在结构指导下发现具有抗诺卡氏菌活性的新型 dUTP 酶抑制剂。

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zhi-Zheng Wang, Jun Weng, Jing Qi, Xin-Xin Fu, Ban-Bin Xing, Yang Hu, Chun-Hsiang Huang, Chin-Yu Chen, Zigong Wei
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引用次数: 0

摘要

由诺卡菌引起的人畜共患疾病日益严重。但常用的抗生素药物往往会导致耐药性。N. seriolae dUTPase(NsdUTPase)在诺卡氏菌的增殖过程中起着关键作用,被认为是一个有效的药物靶点。然而,有关 NsdUTPase 抑制剂的报道却很少。在这项研究中,我们发现了一系列新型 NsdUTPase 抑制剂来对抗诺卡氏菌。我们首次公布了 NsdUTPase 的晶体结构,并进行了基于结构的计算设计。化合物 4b 和 12b 对 NsdUTPase 具有良好的活性(IC50 = 0.99 μM 和 0.7 μM)。此外,它们还表现出满意的抗诺卡氏菌活性(MIC 值范围为 0.5 至 2 mg/L)和较低的细胞毒性,优于已批准的药物土霉素和氟苯尼考。分子建模研究表明,疏水作用可能是配体结合的主要原因。我们的研究结果表明,NsdUTP 酶抑制剂可能是抑制诺卡氏菌的有效方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structure-guided discovery of novel dUTPase inhibitors with anti-Nocardia activity by computational design.

The zoonosis caused by Nocardia is increasing seriously. But commonly used antibiotic drugs often lead to resistance. N. seriolae dUTPase (NsdUTPase) plays a key role in the proliferation of Nocardia, and was regarded as a potent drug target. However, there was little report about the NsdUTPase inhibitors. In this study, we discovered a series of novel NsdUTPase inhibitors to fight against Nocardia. The first crystal structure of NsdUTPase was released, and a structure-based computational design was performed. Compounds 4b and 12b exhibited promising activities towards NsdUTPase (IC50 = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti-Nocardia activity (MIC value ranges from 0.5 to 2 mg/L) and low cytotoxicity, which were better than approved drugs oxytetracycline and florfenicol. Molecular modelling study indicated that hydrophobic interaction might be the main contribution for ligand binding. Our results suggested that NsdUTPase inhibitors might be a useful way to repress Nocardia.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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