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

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Discovering small molecules that target allosteric sites on protein kinases is a significant challenge.
• Currently, only a limited number of highly selective allosteric modulators exist for kinases.

Purpose of the Study:

• To develop a general method for identifying allosteric modulators for protein kinases.
• To identify ligands for the allosteric peptide-binding site (PIF pocket) on PDK1.

Main Methods:

• Utilized virtual screening against an ensemble of crystal structures and comparative models.
• Employed an analog-by-catalog search for ligand optimization.
• Confirmed ligand binding poses via X-ray crystallography.

Main Results:

• Identified novel ligands targeting the PIF pocket of PDK1.
• Optimized ligands resulted in compound 4 with an 8 μM binding affinity for PDK1.
• Determined the crystal structure of PDK1 in complex with compound 4, validating the docking poses.

Conclusions:

• The developed virtual screening approach is effective for discovering allosteric modulators.
• The PIF pocket, a recurring feature in kinases (helix αC patch), is a viable target for allosteric modulation.
• This method holds promise for discovering allosteric modulators for a wider range of kinases.