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基于醇的新型SIRT2抑制剂通过分子建模研究和酶检测发现

Elena Abbotto¹, Beatrice Casini², Francesco Piacente¹

¹Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy.

Pharmaceuticals (Basel, Switzerland)

|September 28, 2023

概括

研究人员对癌症和神经退行性疾病的sirtuin 2抑制剂 (SIRT2is) 进行了探索. 基于结构的药物设计确定了强度抑制的关键相互作用,导致有希望的双重HSP70/SIRT2抑制剂.

科学领域:

药用化学医学化学
结构生物学结构生物学
药物发现药物发现药物发现

背景情况:

赛尔图因小分子抑制剂 (SIRTI) 对癌症,神经退行性疾病,糖尿病和自身免疫性疾病具有治疗潜力.
有关SIRT2调节器的兴趣很大,现有的X晶体学数据使基于结构的研究成为可能.

研究的目的:

进行基于结构的研究以确定新型SIRT2抑制剂.
通过选内部图书馆来探索双作用HSP70/SIRT2抑制剂.

主要方法:

从文献中收集了116种已知的SIRT2抑制剂,用于对抗SIRT2的分子对接 (4RMG,5MAT PDB代码).
分析了关键的结合相互作用,包括范德瓦尔斯和 π-π 堆叠与特定残留物 (Tyr104, Phe119, Phe234, Phe235).
选了以前作为HSP70抑制剂研究的内部化合物库 (1a-7a).

主要成果:

在SIRT2口袋中确定了关键的结合相互作用,这对于高抑制活性至关重要.
化合物1a-7a被评估为双重HSP70/SIRT2抑制潜力.
化合物2a和7a从生物和酶分析中出现了最有前途的衍生物.

结论:

基于结构的分析提供了对SIRT2抑制的关键相互作用的见解.
化合物2a和7a显示出作为双重HSP70/SIRT2抑制剂的显著潜力.
这项研究验证了发现针对SIRT2和潜在的其他相关酶的新型治疗剂的战略.

关键词:

在HSP70中,HSP70是在SIRT2中,SIRT2是SIRT2.酶性检测试验酶性检测试验抑制剂抑制剂的作用分子对接的分子对接.这里是Sirtuin.虚拟选是虚拟的选.

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