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

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• 作者：Carolina M. Avila ; Alex ; ra B. Lopes ; Arlan S. Gon&#xe7 ; alves ; Le ; ro L. da Silva ; Nelilma C. Romeiro ; Ana Luisa P. Mir ; a ; Carlos M.R. Sant’ ; Anna ; Eliezer J. Barreiro ; Carlos A.M. Fraga
• 关键词：anti-Inflammatory ; IKK-β ; inhibitor ; Molecular docking ; N-Acylhydrazone ; Privileged structure ; Structure-based design
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 2011
• 年：2011
• 卷：46
• 期：4
• 页码：1245-1253
• 全文大小：1520 K

文摘

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.