Design, synthesis and biological characterization of novel inhibitors of CD38

Min Dong, Yuan Qi Si, Shuang Yong Sun, Xiao Ping Pu, Zhen Jun Yang, Liang Ren Zhang, Li He Zhang*, Fung Ping Leung, Connie Mo Ching Lam, Anna Ka Yee Kwong, Jianbo Yue, Yeyun Zhou, Irina A. Kriksunov, Quan Hao, Hon Cheung Lee

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

32 Citations (Scopus)


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 Ca2+ messenger molecule, cyclic ADP-ribose, from NAD+. It is well established that this novel Ca2+ 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 (Compound1-14). A number of these compounds exhibited moderate inhibition of the NAD+ utilizing activity of CD38, with Compound4 showing the highest potency. The crystal structure of CD38/Compound4 complex and computer simulation of Compound7 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 Compounds4 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.

Original languageEnglish
Pages (from-to)3246-3257
Number of pages12
JournalOrganic and Biomolecular Chemistry
Issue number9
Publication statusPublished - 7 May 2011

Scopus Subject Areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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