jm8b00256_si_002.pdf (1.84 MB)
Structural Insights on Fragment Binding Mode Conservation
journal contributionposted on 2018-06-15, 00:00 authored by Malgorzata N. Drwal, Guillaume Bret, Carlos Perez, Célien Jacquemard, Jérémy Desaphy, Esther Kellenberger
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.
binding pocketchemical changesfragment binding modes1832 drug-like ligandsBinding modesProtein Data BankFragment Binding Mode Conservation Aimingstructure-based drug design1079 fragmentsinteraction coveragefragment binding modebinding modesdata analysis126 crystallization additivesStructural Insights235 proteinsdrug-like superstructures bindingscale analysisfragment bindingligandable targets