The kinetics of binding to p38MAP kinase by analogues of BIRB 796.
BIRB 796, a member of the N-pyrazole-N'-naphthly urea class of p38MAPK inhibitors, binds to the kinase with both slow association and dissociation rates. Prior to binding, the kinase undergoes a reorganization of the activation loop exposing a critical binding domain. We demonstrate that, independent of the loop movement, association rates are governed by low energy conformations of the inhibitor and polar functionality on the tolyl ring. As anticipated, the dissociation rates of the inhibitors from the kinase are slowed by lipophilic and hydrogen bond interactions. The value of structure-kinetic relationships (SKR) in drug design is discussed.
Regan
John
J
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, USA. jregan@rdg.boehringer-ingelheim.com
Pargellis
Christopher A
CA
Cirillo
Pier F
PF
Gilmore
Thomas
T
Hickey
Eugene R
ER
Peet
Gregory W
GW
Proto
Alfred
A
Swinamer
Alan
A
Moss
Neil
N
D001327:Autoimmune Diseases / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases; D010671:Phenylurea Compounds
D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D009281:Naphthalenes; D011720:Pyrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C452139:doramapimod; D010671:Phenylurea Compounds