Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.

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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