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

ABSTRACT: 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 ?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 ?C patch, this approach may enable the discovery of allosteric modulators for other kinases.

SUBMITTER: Rettenmaier TJ

PROVIDER: S-EPMC5099076 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Rettenmaier T Justin TJ Fan Hao H Karpiak Joel J Doak Allison A Sali Andrej A Shoichet Brian K BK Wells James A JA

Journal of medicinal chemistry 20151012 20

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 pock ...[more]

PMID: 26443011

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Dataset Information

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

Publications

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

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