title: Design, synthesis and biological characterization of novel inhibitors of CD38.
abstract: 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.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Min
authors: M
authors: Dong
authors: Yuan-Qi
authors: YQ
authors: Si
authors: Shuang-Yong
authors: SY
authors: Sun
authors: Xiao-Ping
authors: XP
authors: Pu
authors: Zhen-Jun
authors: ZJ
authors: Yang
authors: Liang-Ren
authors: LR
authors: Zhang
authors: Li-He
authors: LH
authors: Zhang
authors: Fung Ping
authors: FP
authors: Leung
authors: Connie Mo Ching
authors: CM
authors: Lam
authors: Anna Ka Yee
authors: AK
authors: Kwong
authors: Jianbo
authors: J
authors: Yue
authors: Yeyun
authors: Y
authors: Zhou
authors: Irina A
authors: IA
authors: Kriksunov
authors: Quan
authors: Q
authors: Hao
authors: Hon Cheung
authors: HC
authors: Lee
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D051381:Rats
chemical_list: D051997:ADP-ribosyl Cyclase 1