Paper Citing NAMD - Abstract
Lafleur, Karine; Huang, Danzhi; Zhou, Ting; Caflisch, Amedeo; Nevado, Cristina
Structure-Based Optimization of Potent and Selective Inhibitors of the Tyrosine Kinase Erythropoietin Producing Human Hepatocellular Carcinoma Receptor B4 (EphB4)
JOURNAL OF MEDICINAL CHEMISTRY, 52:6433-6446, OCT 22 2009
The tyrosine kinase EphB4 is an attractive target for drug design because of its recognized role in cancer-related angiogenesis. Recently, a series of commercially available xanthine derivatives were identified as micromolar inhibitors of EphB4 by high-throughput fragment-based docking into the ATP-binding site of the kinase domain. Here, we have exploited the binding mode obtained by automatic docking for the optimization of these EphB4 inhibitors by chemical synthesis. Addition of only two heavy atoms, methyl and hydroxyl groups, to compound 4 has yielded the single-digit nanomolar inhibitor 66, with a remarkable improvement of the ligand efficiency from 0.26 to 0.37 kcal/(mol per non-hydrogen atom). Compound 66 shows very high affinity for a few other tyrosine kinases with threonine as gatekeeper residue (Abl, Lck, and Src). On the other hand, it is selective against kinases with a larger gatekeeper. A 45 ns molecular dynamics (MD) simulation of the complex of EphB4 and compound 66 provides further validation of the binding mode obtained by fragment-based docking.
