Structural Insights on Fragment Binding Mode Conservation,Journal of Medicinal Chemistry

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Structural Insights on Fragment Binding Mode Conservation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-15 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00256
Malgorzata N. Drwal ₁ , Guillaume Bret ₁ , Carlos Perez ₂ , Célien Jacquemard ₁ , Jérémy Desaphy ₃ , Esther Kellenberger ₁

Affiliation

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.

中文翻译：

关于片段结合模式保守性的结构见解

为了深入了解片段与可配体靶标的结合，我们对蛋白质数据库进行了大规模分析。比较了1832种药物样配体和1079个片段与235种蛋白质的结合方式。我们观察到片段的结合模式及其与相同蛋白质结合的类药物超结构被最保守，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，可以容许片段中的小化学变化。该观察结果的例外通常涉及分子的构象变异性。我们的数据分析还表明，只要在蛋白质中结晶了足够多的片段，就可以实现结合袋的良好相互作用。最后的，

更新日期：2018-06-15

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