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基于结构的计算机辅助药物设计,以确定阿斯巴拉基尼尔内多酶抑制剂的潜在分子

Meenakshi Singh¹, Ian Steinke¹, Rajesh H Amin¹

¹Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA.

Journal of biomolecular structure & dynamics

|October 15, 2024

概括

研究人员确定了六种新型小分子 (AEPI-1到AEPI-6),可以有效抑制阿斯巴拉基尼尔内酸酶 (AEP),这种酶与阿尔茨海默氏症等神经退行性疾病有关. 这些AEP抑制剂具有很高的亲和力和稳定性,为新药开发提供了一个有前途的途径.

科学领域:

生物化学生物化学
神经科学是一个神经科学.
计算化学计算化学

背景情况:

阿斯巴拉基尼尔内酸酶 (AEP) 涉及与蛋白质病变相关的神经退行性疾病,如阿尔茨海默病 (AD) 和前性痴呆症 (FTD).
AEP活动导致蛋白质聚合物的形成和随后的神经退行,这代表了大量未满足的医疗需求.
目前,没有经过临床批准的小分子抑制剂用于AEP.

研究的目的:

设计和开发新的小分子抑制剂用于阿斯巴拉基尼尔内酸酶 (AEP).
为了确定潜在的药物候选者,针对AEP的蛋白质分解活性用于神经退行性疾病的治疗.

主要方法:

使用基于结构的计算机辅助药物设计 (SB-CADD).
虚拟高吞吐量选 (vHTS) 来自中枢神经系统专注的数据库中的1000万种化合物.
进行了分子对接 (glide XP),MM-GBSA结合能计算和50 ns分子动力学 (MD) 模拟.

主要成果:

通过vHTS.TS确定了60个得分最高的配体.
六种阿斯巴拉基尼尔内多酶抑制剂 (AEPI-1至AEPI-6) 显示出对AEP催化三元组的高度亲和力.
MD模拟证实了所有六个命中者的稳定复合体,AEPI-2显示了最高的结合口袋稳定性.
分析显示,这些抑制剂与关键活性部位区域结合,包括β螺旋和S1口袋.

结论:

从AEPI-1到AEPI-6是针对AEP的有希望的药物候选者.
这些分子在AEP活性部位内表现出有利的结合特性和稳定性.
这些发现支持这些抑制剂在开发针对AEP相关的神经退行性疾病的新疗法方面的潜力.

关键词:

亚斯巴拉基尼尔内多胺酶抑制剂 "三角洲分泌酶"是什么意思在Legumain中使用.动态交叉相关性矩阵.分子动态模拟的分子动态模拟.主要组件分析的主要组件分析概率密度函数是一个概率密度函数.虚拟高吞吐量选虚拟高吞吐量选

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