Structural Insights on Fragment Binding Mode Conservation

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.