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Discovery of a Novel Chemotype of Tyrosine Kinase Inhibitors by Fragment-Based Docking and Molecular Dynamics

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Department of Biochemistry and Department of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
*C.N.: phone, (41) 446353945; fax, (41) 446353948; e-mail, [email protected]. A.C.: phone, (41) 446355521; fax, (41) 446356862; e-mail, [email protected]
Cite this: ACS Med. Chem. Lett. 2012, 3, 10, 834–838
Publication Date (Web):August 23, 2012
https://doi.org/10.1021/ml3001984
Copyright © 2012 American Chemical Society
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Abstract

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We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 μM to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 Å resolution.

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Chemical synthesis, crystallization, similarity comparison with known Eph inhibitors, description of the algorithm used to decompose a compound library, distribution of physicochemical properties of the library of anchor fragments, and MD screening of candidate compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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The atomic coordinates and structure factors of EphA3 in complex with compound 7 have been deposited with the Protein Data Bank as entry 4G2F.

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