Aldeghi Matteo, Ross Gregory A, Bodkin Michael J, Essex Jonathan W, Knapp Stefan, Biggin Philip C
Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
Commun Chem. 2018 Apr 5;1. doi: 10.1038/s42004-018-0019-x.
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.
在药物设计中，保守水分子备受关注，因为此类水分子的取代可导致更高亲和力的配体，在某些情况下，还有助于提高选择性。溴结构域是参与基因转录表观遗传调控的小蛋白质结构域，其结合口袋中显示出由四个保守水分子构成的网络，最近一直是药物化学研究的重点。理解为何某些溴结构域有可取代的水分子而其他的没有极具挑战性，并且给定溴结构域中的哪些水分子可作为取代目标仍不清楚。在此，我们通过使用全原子巨正则蒙特卡罗模拟的结合自由能计算来估计35个溴结构域中保守水分子的稳定性。发现与现有实验证据有令人鼓舞的定量一致性。因此，我们讨论了不同溴结构域中水分子取代的预期难易程度及其对配体选择性的影响。
