1303528-49-5Relevant articles and documents
Design, synthesis and biological characterization of novel inhibitors of CD38
Dong, Min,Si, Yuan-Qi,Sun, Shuang-Yong,Pu, Xiao-Ping,Yang, Zhen-Jun,Zhang, Liang-Ren,Zhang, Li-He,Leung, Fung Ping,Lam, Connie Mo Ching.,Kwong, Anna Ka Yee,Yue, Jianbo,Zhou, Yeyun,Kriksunov, Irina A.,Hao, Quan,Cheung Lee, Hon
, p. 3246 - 3257 (2011/06/10)
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.
