Matteo Aldeghi, Gregory A. Ross, Michael J. Bodkin, Jonathan W. Essex, Stefan Knapp & Philip C. Biggin

doi:10.1038/s42004-018-0019-x

生物物理化学；计算化学

Published:

Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

本月初《通讯-化学》发表的一项研究Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo报道了一种采用巨正则蒙特卡罗方法，对布罗莫结构域结合口袋中水的稳定性进行大规模分析的研究，从而辅助相关药物设计。

守恒水分子在药物设计领域扮演着重要角色，因为置换这样的水可以获得更高亲和力的配体，并且在某些情况下有助于选择性。布罗莫结构域是参与基因转录表观遗传调控的小蛋白质结构域，它们的结合口袋中存在四个守恒水分子的网络，并且最近一直是药物化学努力的焦点。了解为什么某些布罗莫结构域具有可置换的水分子，而其他结构则不具有，有着极大的挑战性，并且人们也不清楚结构域中的哪些水分子可能成为置换的目标。

来自英国牛津大学的Matteo Aldeghi和Philip C. Biggin及同事通过使用全原子巨正则蒙特卡罗模拟，来计算结合自由能，以估计35个布罗莫结构域中守恒水分子的稳定性。作者发现计算结果与已有的实验证据可以定量地吻合。综上，作者讨论了在不同的布罗莫结构域中预期的水置换容易程度以及对配体选择性的影响。（来源：科学网）