Structural highlights
Publication Abstract from PubMed
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 muM 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 A resolution.
Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics.,Zhao H, Dong J, Lafleur K, Nevado C, Caflisch A ACS Med Chem Lett. 2012 Aug 23;3(10):834-8. doi: 10.1021/ml3001984. eCollection, 2012 Oct 11. PMID:24900387[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhao H, Dong J, Lafleur K, Nevado C, Caflisch A. Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics. ACS Med Chem Lett. 2012 Aug 23;3(10):834-8. doi: 10.1021/ml3001984. eCollection, 2012 Oct 11. PMID:24900387 doi:http://dx.doi.org/10.1021/ml3001984
