School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
Chem Soc Rev. 2021 Aug 21;50(16):9104-9120. doi: 10.1039/d0cs00151a. Epub 2021 Jun 29.
The fundamental importance of water molecules at drug-protein interfaces is now widely recognised and a significant feature in structure-based drug design. Experimental methods for analysing the role of water in drug binding have many challenges, including the accurate location of bound water molecules in crystal structures, and problems in resolving specific water contributions to binding thermodynamics. Computational analyses of binding site water molecules provide an alternative, and in principle complete, structural and thermodynamic picture, and their use is now commonplace in the pharmaceutical industry. In this review, we describe the computational methodologies that are available and discuss their strengths and weaknesses. Additionally, we provide a critical analysis of the experimental data used to validate the methods, regarding the type and quality of experimental structural data. We also discuss some of the fundamental difficulties of each method and suggest directions for future study.
水分子在药物-蛋白质界面的重要性现已得到广泛认可，并且是基于结构的药物设计的一个重要特征。分析水在药物结合中作用的实验方法存在许多挑战，包括在晶体结构中准确确定结合水的位置，以及解决特定水对结合热力学的贡献的问题。对结合位点水分子的计算分析提供了一种替代方法，并且原则上提供了完整的结构和热力学图像，其在制药行业中的应用现已很普遍。在这篇综述中，我们描述了现有的计算方法，并讨论了它们的优缺点。此外，我们还对用于验证方法的实验数据进行了批判性分析，涉及实验结构数据的类型和质量。我们还讨论了每种方法的一些基本困难，并提出了未来研究的方向。
