The kinetics of binding to p38MAP kinase by analogues of BIRB 796.

Article Details

Citation

Regan J, Pargellis CA, Cirillo PF, Gilmore T, Hickey ER, Peet GW, Proto A, Swinamer A, Moss N

The kinetics of binding to p38MAP kinase by analogues of BIRB 796.

Bioorg Med Chem Lett. 2003 Sep 15;13(18):3101-4.

PubMed ID
12941343 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
1-(5-Tert-Butyl-2-Methyl-2h-Pyrazol-3-Yl)-3-(4-Chloro-Phenyl)-UreaMitogen-activated protein kinase 14Kd (nM)1190N/AN/ADetails
DoramapimodMitogen-activated protein kinase 14Kd (nM)0.098N/AN/ADetails