Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis

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• 作者：Xiaoai Wu^a ; ^b ; ^&dagger ; ; Zhen Fang^a ; ^&dagger ; ; Bo Yang^c ; ^d ; ^&dagger ; ; Lei Zhong^a ; Qiuyuan Yang^a ; Chunhui Zhang^a ; Shenzhen Huang^a ; Rong Xiang^e ; Takayoshi Suzuki^f ; Lin-Li Li^c ; ^{ysylilinli@sina.com" class="auth_mail" title="E-mail the corresponding author} ; Sheng-Yong Yang^a ; ^{yangsy@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：KDM5A ; Histone lysine demethylation ; Structure&ndash ; activity relationship ; Epigenetics ; Small molecule inhibitor
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：26
• 期：9
• 页码：2284-2288
• 全文大小：1745 K

文摘

Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure–activity relationship (SAR) analysis were carried out to the most active hit compound, boldFont">9 (IC₅₀: 2.3 μM), which led to the discovery of several new KDM5A inhibitors. Among them, compound boldFont">15e is the most potent one with an IC₅₀ value of 0.22 μM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound boldFont">15e could be taken as a good lead compound for further studies.