4G2F
Human EphA3 kinase domain in complex with compound 7
Summary for 4G2F
| Entry DOI | 10.2210/pdb4g2f/pdb |
| Descriptor | EPH receptor A3, 1-amino-5-(5-hydroxy-2-methylphenyl)-7,8,9,10-tetrahydropyrimido[4,5-c]isoquinolin-6(5H)-one (3 entities in total) |
| Functional Keywords | receptor tyrosine kinase, atp binding, phosphorylation, membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40780.54 |
| Authors | Dong, J.,Caflisch, A. (deposition date: 2012-07-12, release date: 2012-10-24, Last modification date: 2023-11-08) |
| Primary citation | 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., 3:834-838, 2012 Cited by PubMed 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 1.7 Å resolution. PubMed: 24900387DOI: 10.1021/ml3001984 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.699 Å) |
Structure validation
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