Structure-based design and biological profile of (E)-N-(4-Nitrobenzylidene)-2-naphthohydrazide, a novel small molecule inhibitor of IκB kinase-β

In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-beta inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-beta active site, and a privileged structure template yielded a novel IKK-beta inhibitor scaffold with significant selectivity over IKK-alpha and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-beta 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-beta inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates. (c) 2011 Elsevier Masson SAS. All rights reserved.