一个受体的功能反应是由连接体结合的热力学决定的吗?
Martin Vögele1, Bin W Zhang1, Jonas Kaindl2
1Schrödinger, Inc., 1540 Broadway 24th Floor, New York, New York 10036, United States.
Journal of chemical theory and computation
|November 9, 2023
概括
结合热力学通过分析与不同蛋白质构成的连接体相互作用,准确地预测药物疗效. 这种方法通过对关键药物标分类激动剂和对抗剂来增强药物发现.
科学领域:
- 计算化学是一种计算化学.
- 药理学 药理学是指药理学的学科.
- 生物物理学的生物物理.
背景情况:
- 有效的药物需要强大的标结合和蛋白质活性调节.
- 蛋白质构成的变化对于药物疗效至关重要,但很难模拟.
- 热力学原理表明,结合的自由能量与连接体的有效性之间存在联系.
研究的目的:
- 为了验证结合热力学可以预测药物疗效的假设.
- 提出一个使用结合自由能量的协议,以推断连接剂的疗效.
- 评估这种方法在各种重要药物标中的性能.
主要方法:
- 应用绝对有约束力的自由能量扰动方法.
- 模拟的配体与八个G蛋白结合受体和一个核受体的活性和非活性状态结合.
- 利用精心设计的束装置来建模形状组合.
主要成果:
- 结合热力学被证明是连接剂有效性的强有力的预测因素.
- 该方法在分类激动剂和抗剂方面取得了高性能.
- 跨多种受体家族的成功应用,包括GPCR和核受体.
结论:
- 约束热力学提供了一个强大的方法来预测药物的疗效.
- 这种方法可以显著改善潜在候选药物的分类.
- 该协议适用于重要的药物标,有助于药物发现和开发.
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