Abstract
In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-β inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-β active site, and a privileged structure template yielded a novel IKK-β inhibitor scaffold with significant selectivity over IKK-α and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-β inhibition, molecular dynamics simulations of LASSBio-1524 (3) were performed. The NAH derivative LASSBio-1524 (3), was able to suppress arachidonic acid-induced edema formation in a dose-dependent manner, demonstrating an in vivo anti-inflammatory effect. The molecular architecture of this novel, low-molecular weight IKK-β inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Anti-Inflammatory Agents / chemical synthesis
-
Anti-Inflammatory Agents / chemistry
-
Anti-Inflammatory Agents / pharmacology
-
Anti-Inflammatory Agents / therapeutic use
-
Benzylidene Compounds / chemical synthesis
-
Benzylidene Compounds / chemistry*
-
Benzylidene Compounds / pharmacology*
-
Benzylidene Compounds / therapeutic use
-
Catalytic Domain
-
Cell Line
-
Drug Design*
-
Edema / chemically induced
-
Edema / drug therapy
-
Female
-
Humans
-
Hydrazones / chemical synthesis
-
Hydrazones / chemistry*
-
Hydrazones / pharmacology*
-
Hydrazones / therapeutic use
-
I-kappa B Kinase / antagonists & inhibitors*
-
I-kappa B Kinase / chemistry
-
Ligands
-
Male
-
Mice
-
Molecular Dynamics Simulation
-
Molecular Sequence Data
-
Molecular Weight
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Kinase Inhibitors / therapeutic use
Substances
-
Anti-Inflammatory Agents
-
Benzylidene Compounds
-
Hydrazones
-
Ligands
-
N-(4-nitrobenzylidene)-2-naphthohydrazide
-
Protein Kinase Inhibitors
-
I-kappa B Kinase