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学科主题: 药学
题名:
Design, synthesis and biological characterization of novel inhibitors of CD38
作者: Dong, Min1; Si, Yuan-Qi1; Sun, Shuang-Yong1; Pu, Xiao-Ping1; Yang, Zhen-Jun1; Zhang, Liang-Ren1; Zhang, Li-He1; Leung, Fung Ping2; Lam, Connie Mo Ching.2; Kwong, Anna Ka Yee2; Yue, Jianbo2; Zhou, Yeyun3; Kriksunov, Irina A.3; Hao, Quan2; Lee, Hon Cheung2
刊名: ORGANIC & BIOMOLECULAR CHEMISTRY
发表日期: 2011
DOI: 10.1039/c0ob00768d
卷: 9, 期:9, 页:3246-3257
收录类别: SCI ; IC
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Organic
研究领域[WOS]: Chemistry
关键词[WOS]: CYCLIC ADP-RIBOSE ; ADENINE-DINUCLEOTIDE ; CRYSTAL-STRUCTURE ; BASIC SCIENCE ; NAADP ; DIFFERENTIATION ; IDENTIFICATION ; GLYCOHYDROLASE ; STIMULATION ; CONTRACTION
英文摘要:

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.

语种: 英语
所属项目编号: NSFC-RGC 20831160506 ; N_HKU 722/08 ; 769107 ; 768408 ; 769309 ; 770610 ; RR001646
项目资助者: National Natural Sciences Foundation of China ; NSFC/RGC ; General Research Fund of Hong Kong ; NIH
WOS记录号: WOS:000289488000024
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/56063
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China
3.Cornell Univ, Cornell High Energy Synchrotron Source, MacCHESS, Ithaca, NY 14853 USA

Recommended Citation:
Dong, Min,Si, Yuan-Qi,Sun, Shuang-Yong,et al. Design, synthesis and biological characterization of novel inhibitors of CD38[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2011,9(9):3246-3257.
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