在碎片分子轨道方法中使用冷域和部分模量体方法的几何优化:对蛋白质质结合位点的实现,基准和应用
Koji Okuwaki1,2,3,4,5, Naoki Watanabe6, Koichiro Kato7
1Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Osaka, Suita 565-0871, Japan.
Journal of chemical information and modeling
|December 2, 2024
概括
新的冷域和部分二分体 (FDPD) 方法加速了大型分子系统的几何优化. 这种计算化学方法通过改善结构-活性关系来增强基于结构的药物发现.
科学领域:
- 计算化学的计算化学
- 分子建模分子建模
- 药物发现 药物发现 药物发现
背景情况:
- 碎片分子轨道 (FMO) 方法与冷域 (FD) 近似为大型系统几何优化提供了效率.
- 现有的FD配方,包括冷域二分子 (FDD),已经建立了计算效率.
研究的目的:
- 实施和评估一种用于分子几何优化的新型冷域和部分二分体 (FDPD) 方法.
- 评估FDPD方法在为药物发现应用提炼蛋白质 - 配体复合物的性能.
主要方法:
- 冷域和部分二分体 (FDPD) 方法的实施,这是冷域近似的变化.
- 应用FDPD/HF/6-31G*用于优化蛋白质连接体复合物的几何,包括β2-上腺素受体,人类雌激素受体和流感病毒神经aminidase.
- 为了分析结构-活性关系,FDPD/HF/6-31G*和FMO-MP2/6-31G*对氨酸-氨酸激酶Pim1及其抑制剂的计算.
主要成果:
- 与传统方法相比,FDPD方法实现了将近50%的计算时间减少,以优化大型G蛋白结合受体的活性位点.
- FDPD优化通过放松固态排斥和优化蛋白质-连接体复合体中的结合来优化精炼的晶体结构.
- 在FDPD计算中扩展优化区域显著改善了pIC50和连接体结合能量的相关性,增强了结构-活性关系.
结论:
- FDPD方法为分子几何优化提供了一个计算效率高,准确的方法.
- 这种方法在基于结构的药物发现中显示出对高精度结构精细化的显著前景.
- 通过FDPD优化改进结构-活性关系分析,可以加速识别潜在的候选药物.
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