Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 20, Pages 8285-8291Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01216
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Funding
- NIH [R01 CA136779, GM59957, U54 GM093342, F31 CA180378]
- Krevans fellowship
- UCSF
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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 mu M 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 alpha C patch, this approach may enable the discovery of allosteric modulators for other kinases.
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