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.

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.

MeSH terms

  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Magnetic Resonance Spectroscopy / methods*
  • Magnetic Resonance Spectroscopy / standards
  • Models, Molecular*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protons
  • Reference Standards
  • Structure-Activity Relationship

Substances

  • Intracellular Signaling Peptides and Proteins
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Protons
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases