Mining the PDB for Tractable Cases Where X‑ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein–Protein Inhibitors: Two Test Cases Illustrated by IL1β-IL1R and p38α–TAB1 Complexes

Nowadays,
it is possible to combine X-ray crystallography and fragment
screening in a medium throughput fashion to chemically probe the surfaces
used by proteins to interact and use the outcome of the screens to
systematically design protein–protein inhibitors. To prove
it, we first performed a bioinformatics analysis of the Protein Data
Bank protein complexes, which revealed over 400 cases where the crystal
lattice of the target in the free form is such that large portions
of the interacting surfaces are free from lattice contacts and therefore
accessible to fragments during soaks. Among the tractable complexes
identified, we then performed single fragment crystal screens on two
particular interesting cases: the Il1β-ILR and p38α-TAB1
complexes. The result of the screens showed that fragments tend to
bind in clusters, highlighting the small-molecule hotspots on the
surface of the target protein. In most of the cases, the hotspots
overlapped with the binding sites of the interacting proteins.