Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.
Article Details
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Constantine KL, Mueller L, Metzler WJ, McDonnell PA, Todderud G, Goldfarb V, Fan Y, Newitt JA, Kiefer SE, Gao M, Tortolani D, Vaccaro W, Tokarski J
Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.
J Med Chem. 2008 Oct 9;51(19):6225-9. doi: 10.1021/jm800747w. Epub 2008 Sep 5.
- PubMed ID
- 18771253 [ View in PubMed]
- Abstract
Fragment-like inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK2) include 5-hydroxyisoquinoline (IC50 approximately 85 microM). Modeling studies identified four possible binding modes for this compound. Two-dimensional (1)H-(1)H NOESY data obtained with selectively protonated samples of MK2 in complex with 5-hydroxyisoquinoline demonstrated that two of the four predicted binding modes are well populated. A second small isoquinoline was subsequently shown to bind in a single mode. NMR and modeling studies using this general approach are expected to facilitate "scaffold hopping" and structure-guided elaborations of fragment-like kinase inhibitor cores.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 2-(2-QUINOLIN-3-YLPYRIDIN-4-YL)-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE MAP kinase-activated protein kinase 2 IC 50 (nM) 8.5 N/A N/A Details