Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking

Finding
small molecules that target allosteric sites remains a
grand challenge for ligand discovery. In the protein kinase field,
only a handful of highly selective allosteric modulators have been
found. Thus, more general methods are needed to discover allosteric
modulators for additional kinases. Here, we use virtual screening
against an ensemble of both crystal structures and comparative models
to identify ligands for an allosteric peptide-binding site on the
protein kinase PDK1 (the PIF pocket). We optimized these ligands through
an analog-by-catalog search that yielded compound 4,
which binds to PDK1 with 8 μM affinity. We confirmed the docking
poses by determining a crystal structure of PDK1 in complex with 4. Because the PIF pocket appears to be a recurring structural
feature of the kinase fold, known generally as the helix αC
patch, this approach may enable the discovery of allosteric modulators
for other kinases.