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

• Published in: European journal of medicinal chemistry 2011-04, Vol.46 (4), p.1245-1253
• Main Authors: Avila, Carolina M., Lopes, Alexandra B., Gonçalves, Arlan S., da Silva, Leandro L., Romeiro, Nelilma C., Miranda, Ana Luisa P., Sant’Anna, Carlos M.R., Barreiro, Eliezer J., Fraga, Carlos A.M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; anti-Inflammatory; 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; IKK-β inhibitor; Ligands; Male; Mice; Molecular docking; Molecular Dynamics Simulation; Molecular Sequence Data; Molecular Weight; N-Acylhydrazone; Privileged structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Structure-based design
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.045

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.