Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics
Title | Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Zhao H., Dong J., Lafleur K., Nevado C., Caflisch A. |
Journal | ACS Medicinal Chemistry Letters |
Volume | 3 |
Issue | 10 |
Pagination | 834-838 |
Date Published | Oct 11 2012 |
Type of Article | Research Article |
ISSN | 1948-5875 |
Keywords | chemotype, EphB4 tyrosine kinase, fragment-based docking, ligand efficiency, molecular dynamics simulations, nanomolar inhibitor |
Abstract | 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 1.7Å resolution. |
DOI | 10.1021/ml3001984 |
pubindex | 0164 |
Alternate Journal | ACS Med. Chem. Lett. |
PubMed ID | 24900387 |
PubMed Central ID | PMC4025670 |
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