title: 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 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.
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94158, United States.|Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
authors.forename: T Justin
authors.initials: TJ
authors.lastname: Rettenmaier
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.|Bioinformatics Institute (BII), Agency for Science, Technology and Research (ASTAR), 30 Biopolis Street, Matrix No. 07-01, 138671, Singapore.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore.
authors.forename: Hao
authors.initials: H
authors.lastname: Fan
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94158, United States.|Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Karpiak
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Doak
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, United States.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000187:drug effects*; D000495:Allosteric Site; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D054852:Small Molecule Libraries; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human