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

被引：24
作者：
Avila, Carolina M. [1 ,2 ]
Lopes, Alexandra B. [1 ,3 ]
Goncalves, Arlan S. [4 ]
da Silva, Leandro L. [1 ,2 ]
Romeiro, Nelilma C. [1 ,5 ]
Miranda, Ana Luisa P. [1 ,2 ]
Sant'Anna, Carlos M. R. [1 ,6 ]
Barreiro, Eliezer J. [1 ,2 ]
Fraga, Carlos A. M. [1 ,2 ]
机构：
[1] Univ Fed Rio de Janeiro, Fac Farm, LASSBio, BR-21941902 Rio de Janeiro, Brazil
[2] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Programa Posgrad Farmacol & Quim Med, BR-21941902 Rio de Janeiro, Brazil
[3] Univ Fed Rio de Janeiro, Inst Quim, Programa Posgrad Quim, BR-21941902 Rio de Janeiro, Brazil
[4] Inst Fed Educ Ciencia & Tecnol Espirito Santo IFE, BR-29215090 Muquicaba Guarapari, Espirito Santo, Brazil
[5] Univ Fed Rio de Janeiro, BR-27930560 Rio de Janeiro, Brazil
[6] UFRRJ, ICE, Dept Quim, BR-23851970 Seropedica, RJ, Brazil
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 46卷 / 04期
关键词：
anti-Inflammatory; IKK-beta inhibitor; Molecular docking; N-Acylhydrazone; Privileged structure; Structure-based design; PARTICLE MESH EWALD; IKK-ALPHA; WATER MODELS; ACID; BIOISOSTERISM; DISCOVERY; DYNAMICS; CHARGES; SUBUNIT; SYSTEM;
D O I：
10.1016/j.ejmech.2011.01.045
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
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收藏
页码：1245 / 1253
页数：9
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