title: Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.
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.
authors.affiliation: Bristol Myers Squibb Research and Development, Princeton, New Jersey 08543, USA. keith.constantine@bms.com
authors.forename: Keith L
authors.initials: KL
authors.lastname: Constantine
authors.forename: Luciano
authors.initials: L
authors.lastname: Mueller
authors.forename: William J
authors.initials: WJ
authors.lastname: Metzler
authors.forename: Patricia A
authors.initials: PA
authors.lastname: McDonnell
authors.forename: Gordon
authors.initials: G
authors.lastname: Todderud
authors.forename: Valentina
authors.initials: V
authors.lastname: Goldfarb
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kiefer
authors.forename: Mian
authors.initials: M
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Tortolani
authors.forename: Wayne
authors.initials: W
authors.lastname: Vaccaro
authors.forename: John
authors.initials: J
authors.lastname: Tokarski
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods* / Q000592:standards; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011522:Protons; D012015:Reference Standards; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011522:Protons; D000099190:MAP-Kinase-Activated Kinase 2