Discovery of dual ZAP70 and Syk kinases inhibitors by docking into a rare C-helix-out conformation of Syk

Hongtao Zhao; Amedeo Caflisch

doi:10.1016/j.bmcl.2014.01.083

Discovery of dual ZAP70 and Syk kinases inhibitors by docking into a rare C-helix-out conformation of Syk

Bioorg Med Chem Lett. 2014 Mar 15;24(6):1523-7. doi: 10.1016/j.bmcl.2014.01.083. Epub 2014 Feb 10.

Authors

Hongtao Zhao¹, Amedeo Caflisch²

Affiliations

¹ Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
² Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.

PMID: 24569110
DOI: 10.1016/j.bmcl.2014.01.083

Abstract

The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation published recently. Interestingly, both compounds are slightly more active on ZAP70 (Zeta-chain-associated protein kinase 70), which is the kinase closest to Syk in the phylogenetic tree of human kinases. Taken together, the docking pose and experimental results suggest that the higher affinity of the inhibitors for ZAP70 than Syk originates from a more populated C-helix-out conformation in ZAP70. The latter observation is congruent with the 100-fold lower intrinsic activity of ZAP70 than Syk, as the C-helix-out conformation is inactive. The pharmacophore features of DFG-in, C-helix-out compounds are analyzed in relation to DFG-out inhibitors.

Keywords: C-helix-out; High-throughput docking; Scoring with solvation; Syk kinase; ZAP70 kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Drug Evaluation, Preclinical
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Molecular Docking Simulation
Protein Binding
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Structure, Secondary
Protein Structure, Tertiary
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Syk Kinase
ZAP-70 Protein-Tyrosine Kinase / antagonists & inhibitors*
ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase
ZAP-70 Protein-Tyrosine Kinase
ZAP70 protein, human