A Perspective on Water Site Prediction Methods for Structure Based Drug Design.
A Perspective on Water Site Prediction Methods for Structure Based Drug Design.
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DOI：
10.2174/1568026617666170427095035
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发表时间：
2017-08
影响因子：
3.4
通讯作者：
A. P. Graves;Ian D. Wall;C. Edge;James M. Woolven;Guanglei Cui;A. Le Gall;Xuan Hong;K. Raha;E. Manas
中科院分区：
文献类型：
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作者：
A. P. Graves;Ian D. Wall;C. Edge;James M. Woolven;Guanglei Cui;A. Le Gall;Xuan Hong;K. Raha;E. Manas
在过去的十年里，已经发展了许多计算方法，试图评估单个水分子在溶质-溶剂界面的热力学性质，以便评估对蛋白质-配体结合的贡献。在某些情况下，这些工具告诉我们已经知道的事情，例如，疏水口袋更喜欢亲油取代基，而在其他情况下，这些方法似乎只有在回溯应用时才增加透明度。因此，我们一直在努力解决如何利用这种方法来理解非直观的结果，并产生否则不会开发的化学想法。在这里，我们提供了我们对这些方法的看法，并描述了结果是如何解释和应用的。我们列举了葛兰素史克和其他地方的例子，强调了水方法是如何被(1)追溯地用于解释非直观的结构-活性关系和(2)未来应用于化学设计的。最后，我们讨论了这个研究领域可以在药物发现研究中产生最大影响的地方。
Over the last decade, a number of computational methods have been developed, which attempt to evaluate the thermodynamic properties of individual water molecules at the solute-solvent interface, in order to assess contributions to protein-ligand binding. In some cases, these tools tell us what we already know, e.g. that hydrophobic pockets prefer lipophilic substituents, and in other cases the methods only seem to add clarity when retrospectively applied. Hence we have grappled with how to utilize such approaches to understand non-intuitive results and to generate chemistry ideas that otherwise would not have been developed. Here we provide our perspective on these methods and describe how results have been interpreted and applied. We include examples from GSK and elsewhere that highlight how water methods have been (1) utilized retrospectively to explain non-intuitive structure- activity relationships and (2) applied prospectively for chemistry design. Finally, we discuss where this field of study could lead to maximal impact in drug discovery research.