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提高HDAC抑制剂查:在对接研究中解决参数化和连接体质突变问题

Rocco Buccheri¹, Alessandro Coco¹, Lorella Pasquinucci¹

¹Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

International journal of molecular sciences

|January 25, 2025

概括

对于结合酶,如脱乙酶 (HDACs),在对接模拟中考虑酸连接体的脱化状态,与质子化状态相比,大大提高了结合自由能量预测的准确性.

科学领域:

计算化学是一种计算化学.
结构生物学是结构生物学.
药物发现药物发现

背景情况:

金属蛋白质,特别是含的酶,如脱乙酶 (HDACs),在预测连接体结合的自由能量方面存在独特的计算挑战.
胺酸是HDAC抑制剂 (HDACi) 中的关键功能组,它们的质子化状态极大地影响了结合部位内的相互作用.

研究的目的:

评估一个协调优化的对接算法,以区分酸联体的质子化和脱质子化状态的能力.
为了确定哪种连接体质子状态产生对接姿势和结合能量的估计,这些估计与HDAC目标的实验数据最相对应.

主要方法:

使用专门的对接算法对酸联体的质子化和脱质子化状态进行系统分析.
在HDAC 2,4和8目标中应用算法.
将对接结果 (姿势和结合能) 与实验数据进行比较,以评估相关性.

主要成果:

胺酸配体的脱化状态始终与所有测试的HDAC标的实验性结合数据有较强的相关性.
无质子联体的平均R平方 (R2) 值为0.80,显著超过质子形式 (R2 = 0.67).

结论:

精确考虑连接体质子化,特别是酸的脱质子化,对于提高涉及HDAC等结合酶的分子对接研究的预测准确度至关重要.
开发的方法为改进虚拟查协议提供了坚实的基础,促进高亲和度HDAC抑制剂的高效发现,并推进金属蛋白向治疗.

关键词:

HDAC 抑制剂的使用绑定预测的自由能量素酸的配合物素酸的配合物金属蛋白质对接的对接点分子对接算法分子对接算法基于结构的药物设计.-结合相互作用的作用.

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