School of Pharmaceutical Science & Technology , Tianjin University , Tianjin 300072 , China.
National Institute of Biological Sciences , Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park , Beijing 102206 , China.
J Chem Inf Model. 2019 Jul 22;59(7):3136-3143. doi: 10.1021/acs.jcim.9b00128. Epub 2019 Jun 25.
Halogen bond interaction between a protein electronegative atom and a ligand halogen atom is increasingly attracting attention in the field of structure-based drug design. Nevertheless, gaps in understanding make it desirable to better examine the role of forces governing the formation of favorable halogen bond interactions, and the development of effective and efficient computational approaches to "design in" favorable halogen bond interactions in lead optimization process are warranted. Here, we analyzed the binding-site water properties of crystal structures with characterized halogen bond interactions between ligand halogen atoms and protein backbone carbonyl groups and, thus, found that halogen atoms involved in halogen bond interactions frequently replace calculated binding-site waters upon ligand binding. Moreover, we observed that the preferential directionality of halogen bond interactions aligns well with the orientations of these replaced waters, and these replaced waters exhibited differential energetic characteristics as compared to waters that are displaced by halogen atoms that do not form halogen bond interactions. Our discovery that replacement of calculated binding-site waters contributes to the formation of favorable halogen bond interactions suggests a practical approach for rational drug design utilizing halogen bond interactions with protein backbone carbonyl groups.
在基于结构的药物设计领域，越来越多的人开始关注蛋白质电负性原子与配体卤原子之间的卤键相互作用。然而，由于理解上的差距，人们希望更好地研究控制有利卤键相互作用形成的力的作用，并开发有效的计算方法，在先导优化过程中“设计”有利的卤键相互作用。在这里，我们分析了具有特征性卤键相互作用的晶体结构的结合部位水性质，发现配体卤原子与蛋白质骨架羰基之间的卤键相互作用，卤原子经常在配体结合时取代计算出的结合部位水。此外，我们观察到卤键相互作用的优先方向性与这些取代水的方向很好地一致，并且与不形成卤键相互作用的卤原子取代的水相比，这些取代的水表现出不同的能量特征。我们发现取代计算出的结合部位水有助于形成有利的卤键相互作用，这表明利用与蛋白质骨架羰基的卤键相互作用进行合理药物设计的一种实用方法。
