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在体中识别20S蛋白酶体-β5亚单元抑制剂,使用基于结构的虚拟查

Ouadie Mohamed El Yaagoubi¹, Wahiba Ezzemani^2,3, Larbi Oularbi^4,5

¹Laboratory of Biochemistry, Environment and Agri-Food (URAC 36), Faculty of Sciences and Techniques-Mohammedia, Hassan II University of Casablanca, Morocco.

Journal of biomolecular structure & dynamics

|July 5, 2023

概括

研究人员发现了针对β5亚单元的新型20S蛋白酶体抑制剂. 三种有前途的候选药物表现出高结合亲和力和低毒性,推动了蛋白酶体抑制剂药物开发.

科学领域:

生物化学生物化学
药理学药理学是指药理学的学科.
计算化学计算化学

背景情况:

蛋白质酶抑制剂通过破坏细胞循环蛋白质降解和诱导亡来表现出抗瘤活性.
20S蛋白质组是经过验证的治疗点,因为它在蛋白质降解和相对抵抗免疫反应方面的重要作用.
针对20S蛋白酶体,特别是β5亚单元,对于开发有效的癌症疗法至关重要.

研究的目的:

为了确定20S蛋白酶体的新型抑制剂,专注于β5亚单元.
利用基于结构的虚拟选和分子对接来预测潜在的候选药物.
为了减少需要对蛋白酶体抑制进行实验验证的化合物的数量.

主要方法:

从ASINEX数据库中选了4961种抗癌分子,使用基于结构的虚拟选.
采用分子对接模拟,包括AutoDock Vina,以评估结合亲和力和验证初始选结果.
对排名最高的化合物进行了分子动力学模拟和计算的ADMET (吸收,分布,新陈代谢,分泌和毒性) 研究.

主要成果:

鉴定了六种具有针对20S蛋白酶体β5亚单元显著相互作用的药物分子.
三种化合物 (BDE 28974746,BDE 25657353,BDD 27844484) 显示出高的结合亲和力和能量,与阳性对照Carfilzomib和Bortezomib相当.
最好的候选药物表现出β5亚单元的稳定性和有利的ADMET配置文件,表明毒性低和良好的药物动力学特性.

结论:

已识别的药物分子代表了开发新的蛋白酶体抑制剂的有希望的线索.
这些化合物在癌症治疗中的治疗潜力需要进一步的生物评估.
计算方法有效地确定了20S蛋白酶体β5亚单元的强效和安全的候选药物.

关键词:

蛋白质组20S是20S的一种.它具有抗癌活性,具有抗癌活性.细胞毒性细胞毒性抑制剂抑制剂抑制剂分子动力学模拟模拟虚拟选-对接虚拟选-对接

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