值得权重:子口袋探索器 (SubPEx),一种权重组合方法,用于增强绑定口袋合规采样
Erich Hellemann1, Jacob D Durrant1
1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
Journal of chemical theory and computation
|August 16, 2023
概括
这项研究引入了Sub-Pocket EXplorer (SubPEx),一种使用加权集体路径采样的新方法,通过探索多个蛋白质结合口袋构造来改进虚拟查. 这提高了与灵活的蛋白质标结合的候选药物的发现.
科学领域:
- 计算化学是一种计算化学.
- 药物发现 药物发现
- 结构生物学是结构生物学.
背景情况:
- 传统的基于结构的虚拟选 (VS) 通常无法识别与替代蛋白质构造结合的连接体.
- 探索蛋白质结合口袋灵活性对于有效的VS至关重要,但对现有方法具有挑战性.
- 集体对接需要强大的口袋采样技术来结合多种构造.
研究的目的:
- 引入Sub-Pocket EXplorer (SubPEx),一种用于加速绑定口袋采样的新方法.
- 通过能够识别针对不同蛋白质构造的配体来增强虚拟选.
- 为了证明SubPEx在药物发现环境中的实用性.
主要方法:
- 子口袋探索器 (SubPEx) 使用权重组合 (WE) 路径采样来有效地探索绑定口袋的结构空间.
- 这种方法可以加快对蛋白质灵活性的采样,这与带结合有关.
- SubPEx应用于热冲击蛋白90,流感神经aminidase和酵母hexokinase 2的研究结果.
主要成果:
- SubPEx有效地加快了绑定口袋采样,解决了集体对接的一个关键局限性.
- 该方法成功地应用于药物发现中至关重要的三个不同的蛋白质.
- 原理证明证明了SubPEx在不同形状状态中识别连接体的潜力.
结论:
- 下口袋探索器 (SubPEx) 提供了一个先进的计算方法,用于基于结构的虚拟选.
- 通过改进口袋采样,SubPEx可以导致发现针对灵活蛋白质的新型候选药物.
- 由于SubPEx的开源可用性,使其在更广泛的药物发现社区中更容易被采用.
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