Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, United States.
Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States.
J Chem Inf Model. 2020 Dec 28;60(12):6612-6623. doi: 10.1021/acs.jcim.0c00877. Epub 2020 Dec 8.
Binding hot spots are regions of proteins that, due to their potentially high contribution to the binding free energy, have high propensity to bind small molecules. We present benchmark sets for testing computational methods for the identification of binding hot spots with emphasis on fragment-based ligand discovery. Each protein structure in the set binds a fragment, which is extended into larger ligands in other structures without substantial change in its binding mode. Structures of the same proteins without any bound ligand are also collected to form an unbound benchmark. We also discuss a set developed by Astex Pharmaceuticals for the validation of hot and warm spots for fragment binding. The set is based on the assumption that a fragment that occurs in diverse ligands in the same subpocket identifies a binding hot spot. Since this set includes only ligand-bound proteins, we added a set with unbound structures. All four sets were tested using FTMap, a computational analogue of fragment screening experiments to form a baseline for testing other prediction methods, and differences among the sets are discussed.
结合热点是蛋白质的区域，由于它们对结合自由能的潜在高贡献，因此具有与小分子结合的高倾向。我们提供了用于测试识别结合热点的计算方法的基准集，重点是基于片段的配体发现。该集中的每个蛋白质结构都结合一个片段，该片段在其他结构中扩展为更大的配体，而其结合模式没有实质性变化。还收集了没有任何结合配体的相同蛋白质的结构以形成未结合的基准。我们还讨论了 Astex 制药公司为验证片段结合的热点和温点而开发的一组基准。该集基于这样的假设，即在同一亚口袋中不同配体中出现的片段可以识别出结合热点。由于该集仅包含配体结合的蛋白质，因此我们添加了一个具有未结合结构的集。使用 FTMap 测试了所有四个集，FTMap 是片段筛选实验的计算模拟，为测试其他预测方法形成了基线，并讨论了集之间的差异。
