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-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. A novel N-acylhydrazone derivative LASSBio-1524 was designed from molecular docking and molecular dynamics studies on the IKK-β active site and identified as selective IKK-β inhibitor (IC 50 = 20 μM). [Display omitted] ► Structure-based design of N-acylhydrazone derivatives as kinase inhibitors. ► Molecular dynamics of LASSBio-1524-IKK-β active site interaction. ► LASSBio-1524 is a selective inhibitor of IKK-β. ► LASSBio-1524 presents a novel molecular architecture for IKK-β inhibiton. ► LASSBio-1524 presents in vivo anti-inflammatory properties.