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通过计算设计,通过结构引导发现具有抗诺卡迪亚活性的新型dUTPase抑制剂

Zhi-Zheng Wang¹, Jun Weng^1,2, Jing Qi¹

¹School of Life Sciences, State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, PR China.

Journal of enzyme inhibition and medicinal chemistry

|October 11, 2024

概括

新型抑制剂向诺卡迪亚串联dUTPase (NsdUTPase) 抗击诺卡迪亚感染. 这些化合物表现出强烈的活性和低细胞毒性,为现有抗生素提供了有希望的替代品.

科学领域:

微生物学微生物学
药物发现药物发现药物发现
结构生物学结构生物学

背景情况:

动物性诺卡迪亚感染是一个越来越令人担忧的问题,通常会遇到抗生素耐药性.
诺卡迪亚串联dUTPase (Ns dUTPase) 对于诺卡迪亚的扩散至关重要,也是潜在的药物标.
报告了针对 Ns dUTPase 的有限抑制剂.

研究的目的:

发现和开发新型的NSdUTPase抑制剂.
通过基于结构的药物设计来对抗诺卡迪亚感染.
为了确定有效和安全的抗诺卡迪亚药物.

主要方法:

确定了 Ns dUTPase 的第一个晶体结构.
采用基于结构的计算设计来识别抑制剂.
评估化合物对Ns dUTPase和Nocardia的活性,以及细胞毒性.

主要成果:

开发了新的Ns dUTPase抑制剂,其中化合物4b和12b具有强烈活性 (IC50 = 0.99 μM和0.7 μM).
这些化合物显示出显著的抗诺卡迪亚活性 (MIC 0.52 mg/L) 和低细胞毒性.
性能超过了已批准的药物氧基环素和花尼的性能.

结论:

Ns dUTPase 抑制剂代表了对诺卡迪亚感染的有前途的治疗策略.
基于结构的设计产生了具有有利安全概况的有效抑制剂.
进一步开发NSdUTPase抑制剂可以解决抗生素耐药性的挑战.

关键词:

计算机辅助药物设计没有心脏.抗生素抗生素是一种抗生素.在 dUTPase 中.

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