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通过虚拟选和结构优化,发现3--1H-5-pyrazolylamides作为PLpro抑制剂

Chengwei Wu¹, Mengdie Ou², Bo Qin²

¹Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.

Bioorganic & medicinal chemistry letters

|June 5, 2025

概括

研究人员确定了一种针对SARS-CoV-2帕帕因类蛋白酶 (PLpro) 的新型支架. 衍生品显示出强大的抑制和低细胞毒性,为新的抗病毒药物开发提供了潜力.

科学领域:

药用化学医学化学
病毒学病毒学
药物发现药物发现药物发现

背景情况:

SARS-CoV-2的帕帕因类蛋白酶 (PLpro) 对于病毒复制至关重要,也是抗病毒疗法的关键标.
识别强效和选择性的PLpro抑制剂对于开发针对SARS-CoV-2的有效治疗方法至关重要.

研究的目的:

发现和开发针对SARS-CoV-2帕帕因类蛋白酶 (PLpro) 的新型抑制剂.
探索作为PLpro抑制剂的新一系列3--1H-5-pyrazolylamide衍生物的结构-活性关系.

主要方法:

虚拟选用于识别针对PLpro.的初始打击化合物.
基于结构的药物设计和药物化学方法被用于合成和优化衍生物.
进行了体外酶定试验,以评估PLpro的抑制活性 (IC50).
进行了细胞毒性测试,以评估化合物的安全性.
使用诸如表面等离子体共振 (SPR) (用KD表示) 等方法来确定结合亲和力.

主要成果:

一个虚拟选的命中,化合物1 (N-(3-(5-amino-1H-pyrazol-3-yl) phenyl) benzenesulfonamide),被确定.
结构修改导致了一系列具有增强PLpro抑制活性的3--1H-5-pyrazolylamide衍生物.
化合物14h和14e表现出显著的PLpro抑制 (IC50分别为14.2微米和12.0微米),细胞毒性较低.
化合物14e,具有硫二甲基组,表现出强烈的结合亲和力 (KD = 1.86 μM).

结论:

3-phenyl-1H-5-pyrazolylamide支架是开发新型SARS-CoV-2 PLpro 抑制剂的有希望的框架.
化合物14e和14h代表了进一步优化为潜在抗病毒药物的主要候选者.
鉴定的衍生品为治疗SARS-CoV-2感染的治疗干预提供了新的途径.

关键词:

3-基-1H-5-pyrazolylamide的使用情况 PLpro PLpro 是一个专业的结构优化优化结构优化虚拟选是一个虚拟的选.

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