Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 22, Issue 1, Pages 211-221Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201503552
Keywords
glycine-rich loop; interaction networks; kinases; molecular recognition; pyrrolidines; water replacement
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Funding
- ETH Research Council
- F. Hoffmann-La Roche, Basel
- German Fonds der Chemischen Industrie
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Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with K-i values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi-facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-p stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach.
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