The kinetics of binding to p38 MAP kinase by analogues of BIRB 796

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 18; pp. 3101 - 3104
• Main Authors: Regan, John, Pargellis, Christopher A., Cirillo, Pier F., Gilmore, Thomas, Hickey, Eugene R., Peet, Gregory W., Proto, Alfred, Swinamer, Alan, Moss, Neil
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2003
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00656-5

BIRB 796, a member of the
N-pyrazole-
N′-naphthly urea class of p38
MAPK 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.
We demonstrate the rates of association and dissociation of binding for analogues of the potent p38
MAP kinase inhibitor, BIRB 796, are influenced by lipophilic and hydrogen bond interactions and low energy conformations of the compounds.