Do Fragments and Crystallization Additives Bind Similarly to Drug-like Ligands?

The success of fragment-based drug
design (FBDD) hinges upon the
optimization of low-molecular-weight compounds (MW < 300 Da) with
weak binding affinities to lead compounds with high affinity and selectivity.
Usually, structural information from fragment–protein complexes
is used to develop ideas about the binding mode of similar but drug-like
molecules. In this regard, crystallization additives such as cryoprotectants
or buffer components, which are highly abundant in crystal structures,
are frequently ignored. Thus, the aim of this study was to investigate
the information present in protein complexes with fragments as well
as those with additives and how they relate to the binding modes of
their drug-like counterparts. We present a thorough analysis of the
binding modes of crystallographic additives, fragments, and drug-like
ligands bound to four diverse targets of wide interest in drug discovery
and highly represented in the Protein Data Bank: cyclin-dependent
kinase 2, β-secretase 1, carbonic anhydrase 2, and trypsin.
We identified a total of 630 unique molecules bound to the catalytic
binding sites, among them 31 additives, 222 fragments, and 377 drug-like
ligands. In general, we observed that, independent of the target,
protein–fragment interaction patterns are highly similar to
those of drug-like ligands and mostly cover the residues crucial for
binding. Crystallographic additives are also able to show conserved
binding modes and recover the residues important for binding in some
of the cases. Moreover, we show evidence that the information from
fragments and drug-like ligands can be applied to rescore docking
poses in order to improve the prediction of binding modes.