- Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.
Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.
Journal of medicinal chemistry (2008-09-06)
Keith L Constantine, Luciano Mueller, William J Metzler, Patricia A McDonnell, Gordon Todderud, Valentina Goldfarb, Yi Fan, John A Newitt, Susan E Kiefer, Mian Gao, David Tortolani, Wayne Vaccaro, John Tokarski
PMID18771253
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.
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