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.
MeSH terms
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Autoimmune Diseases / drug therapy
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Drug Design
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrophobic and Hydrophilic Interactions
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Inhibitory Concentration 50
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Kinetics
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / chemistry
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Mitogen-Activated Protein Kinases / metabolism*
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Naphthalenes / chemistry*
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Naphthalenes / pharmacology
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Protein Binding
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Protein Structure, Tertiary
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Structure-Activity Relationship
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Naphthalenes
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Pyrazoles
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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doramapimod