Discovery of tyrosine kinase inhibitors by docking into an inactive kinase conformation generated by molecular dynamics

TitleDiscovery of tyrosine kinase inhibitors by docking into an inactive kinase conformation generated by molecular dynamics
Publication TypeJournal Article
Year of Publication2012
AuthorsZhao H., Huang D., Caflisch A.
Date Published2012 Nov
Type of ArticleResearch Article
KeywordsDrug Design, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Conformation, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Small Molecule Libraries

Several small molecules that bind to the inactive DFG-out conformation of tyrosine kinases (called type II inhibitors) have shown a good selectivity profile over other kinase targets. To obtain a set of DFG-out structures, we performed an explicit solvent molecular dynamics (MD) simulation of the complex of the catalytic domain of a tyrosine kinase receptor, ephrin type-A receptor 3 (EphA3), and a manually docked type II inhibitor. Automatic docking of four previously reported type II inhibitors was used to select a single snapshot from the MD trajectory for virtual screening. High-throughput docking of a pharmacophore-tailored library of 175,000 molecules resulted in about 4 million poses, which were further filtered by van der Waals efficiency and ranked according to a force-field-based energy function. Notably, around 20 % of the compounds with predicted binding energy smaller than -10 kcal mol-1 are known type II inhibitors. Moreover, a series of 5-(piperazine-1-yl)isoquinoline derivatives was identified as a novel class of low-micromolar inhibitors of EphA3 and unphosphorylated Abelson tyrosine kinase (Abl1). The in silico predicted binding mode of the new inhibitors suggested a similar affinity to the gatekeeper mutant T315I of Abl1, which was verified in vitro by using a competition binding assay. Additional evidence for the type II binding mode was obtained by two 300 ns MD simulations of the complex between N-(3-chloro-4-(difluoromethoxy)phenyl)-2-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)acetamide and EphA3.



Alternate JournalChemMedChem
PubMed ID22976951
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