Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 3, Issue 10, Pages 834-838Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml3001984
Keywords
In silico screening; EphB4 kinase; angiogenesis; cancer; explicit solvent MD
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Funding
- Swiss National Science Foundation
- Sino-Swiss Science and Technology Cooperation
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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 mu M 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 angstrom resolution.
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