| Title | Design, synthesis and biological characterization of novel inhibitors of CD38 |
| Authors | 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 Lee, Hon Cheung |
| Affiliation | Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China. Cornell Univ, Cornell High Energy Synchrotron Source, MacCHESS, Ithaca, NY 14853 USA. |
| Keywords | CYCLIC ADP-RIBOSE ADENINE-DINUCLEOTIDE CRYSTAL-STRUCTURE BASIC SCIENCE NAADP DIFFERENTIATION IDENTIFICATION GLYCOHYDROLASE STIMULATION CONTRACTION |
| Issue Date | 2011 |
| Publisher | organic biomolecular chemistry |
| Citation | ORGANIC & BIOMOLECULAR CHEMISTRY.2011,9,(9),3246-3257. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/156714 |
| ISSN | 1477-0520 |
| DOI | 10.1039/c0ob00768d |
| Indexed | SCI(E) EI PubMed |
| Appears in Collections: | 药学院 天然药物与仿生药物国家重点实验室 |
