Thermal denaturation: a method to rank slow binding, high-affinity P38alpha MAP kinase inhibitors.

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Kroe RR, Regan J, Proto A, Peet GW, Roy T, Landro LD, Fuschetto NG, Pargellis CA, Ingraham RH

Thermal denaturation: a method to rank slow binding, high-affinity P38alpha MAP kinase inhibitors.

J Med Chem. 2003 Oct 23;46(22):4669-75.

PubMed ID

14561086 [ View in PubMed

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Abstract

It has been reported that the diaryl urea class of p38alpha inhibitors binds to p38 map kinase with both high affinity and slow binding kinetics (Pargellis et al. Nat. Struct. Biol. 2002, 9, 268-272). The slow binding kinetics of this class of inhibitors is believed to be the result of binding to an allosteric pocket adjacent to the p38alpha active site. The use of traditional kinetic and equilibrium methods to measure the binding affinity of this class of compounds has created many challenges for determination of structure-activity relationships (SAR). The thermal denaturation method provides a means of measuring high-affinity interactions. In this paper, the method of thermal denaturation will be described as it has been applied to the diaryl urea class of p38 map kinase inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
1-(5-Tert-Butyl-2-Methyl-2h-Pyrazol-3-Yl)-3-(4-Chloro-Phenyl)-Urea	Mitogen-activated protein kinase 14	Kd (nM)	1160	7	23	Details
Doramapimod	Mitogen-activated protein kinase 14	Kd (nM)	0.1	7	23	Details