Dipartimento Farmacochimico, Tossicologico e Biologico, Università di Palermo, Via Archirafi 32, Palermo, Italy.
J Mol Graph Model. 2010 Aug 24;29(1):72-81. doi: 10.1016/j.jmgm.2010.04.008. Epub 2010 May 10.
The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-beta in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-beta inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 inhibitors included in the Binding Database. In order to overcome the difficulty due to the lack of crystallographic data for IKK-beta, a homology model of this protein has been built and validated. The results allowed to study in depth the structural bases for the interaction of each family of inhibitors and provided clues for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting this enzyme.
IKK 激酶家族是一个激动人心的研究领域，因为它在调节 NF-κB 转录因子的活性方面具有重要意义。IKK-β在凋亡或炎症刺激下转录激活中发挥的核心作用的发现，使其成为治疗慢性炎症和癌症的有前途的工具。迄今为止，已经发现并测试了几种 IKK-β抑制剂。在这项工作中，通过应用分子对接和药效团/3D-QSAR 方法对包含在结合数据库中的 141 种抑制剂进行分析，研究了不同类抑制剂与其生物靶标之间的相互作用。为了克服由于缺乏 IKK-β晶体结构数据而导致的困难，构建并验证了该蛋白的同源模型。结果深入研究了每个抑制剂家族相互作用的结构基础，并为进一步的修饰提供了线索，目的是提高针对该酶的设计药物的活性和选择性。
