Laboratoire d'Innovation Thérapeutique , UMR7200, Université de Strasbourg , 74 Route du Rhin , 67401 Illkirch , France.
Eli Lilly Research Laboratories , Avenida de la Industria, 30 , 28108 Alcobendas , Madrid , Spain.
J Med Chem. 2018 Jul 26;61(14):5963-5973. doi: 10.1021/acs.jmedchem.8b00256. Epub 2018 Jul 3.
Aiming at a deep understanding of fragment binding to ligandable targets, we performed a large scale analysis of the Protein Data Bank. Binding modes of 1832 drug-like ligands and 1079 fragments to 235 proteins were compared. We observed that the binding modes of fragments and their drug-like superstructures binding to the same protein are mostly conserved, thereby providing experimental evidence for the preservation of fragment binding modes during molecular growing. Furthermore, small chemical changes in the fragment are tolerated without alteration of the fragment binding mode. The exceptions to this observation generally involve conformational variability of the molecules. Our data analysis also suggests that, provided enough fragments have been crystallized within a protein, good interaction coverage of the binding pocket is achieved. Last, we extended our study to 126 crystallization additives and discuss in which cases they provide information relevant to structure-based drug design.
为了深入了解片段与配体靶标的结合情况，我们对蛋白质数据库进行了大规模分析。比较了 1832 种类似药物的配体和 1079 种片段与 235 种蛋白质的结合模式。我们观察到，片段及其类似药物超结构与同一蛋白质的结合模式大多是保守的，从而为分子生长过程中片段结合模式的保留提供了实验证据。此外，在不改变片段结合模式的情况下，允许片段中的小化学变化。这种观察的例外情况通常涉及分子的构象可变性。我们的数据分析还表明，只要在蛋白质中结晶了足够数量的片段，就可以实现对结合口袋的良好相互作用覆盖。最后，我们将研究扩展到 126 种结晶添加剂，并讨论在哪些情况下它们提供了与基于结构的药物设计相关的信息。
