Format

Send to

Choose Destination
See comment in PubMed Commons below
J Med Chem. 2015 Oct 22;58(20):8285-91. doi: 10.1021/acs.jmedchem.5b01216. Epub 2015 Oct 12.

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

Author information

  • 1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix No. 07-01, 138671, Singapore.
  • 2Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, 117543, Singapore.

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 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.

PMID:
26443011
PMCID:
PMC5099076
DOI:
10.1021/acs.jmedchem.5b01216
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society Icon for PubMed Central
    Loading ...
    Support Center