Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic

作者：Lauber Birgit S; Hardegger Leo A; Asraful Alam K; Lund Bjarte A; Dumele Oliver; Harder Michael; Kuhn Bernd; Engh Richard A^*; Diederich Francois^*

来源：Chemistry - A European Journal, 2016, 22(1): 211-221.

DOI：10.1002/chem.201503552

• glycine-rich loop
• interaction networks
• kinases
• molecular recognition
• pyrrolidines
• water replacement

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.

• 出版日期2016-1-4