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Article: Design, synthesis and biological characterization of novel inhibitors of CD38

TitleDesign, synthesis and biological characterization of novel inhibitors of CD38
Authors
Issue Date2011
PublisherRoyal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/obc
Citation
Organic And Biomolecular Chemistry, 2011, v. 9 n. 9, p. 3246-3257 How to Cite?
AbstractHuman 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 (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. © 2011 The Royal Society of Chemistry.
Persistent Identifierhttp://hdl.handle.net/10722/137500
ISSN
2015 Impact Factor: 3.559
2015 SCImago Journal Rankings: 1.464
ISI Accession Number ID
Funding AgencyGrant Number
National Natural Sciences Foundation of ChinaNSFC-RGC 20831160506
NSFC/RGCN_HKU 722/08
General Research Fund of Hong Kong769107
768408
769309
770610
NIHRR001646
Funding Information:

This study was supported by grants from the National Natural Sciences Foundation of China to LH Zhang (NSFC-RGC 20831160506), and the NSFC/RGC grant N_HKU 722/08 and General Research Fund of Hong Kong: 769107, 768408, 769309, 770610 (to H. C. Lee and Q Hao). MacCHESS is supported by an NIH grant RR001646.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorDong, Men_HK
dc.contributor.authorSi, YQen_HK
dc.contributor.authorSun, SYen_HK
dc.contributor.authorPu, XPen_HK
dc.contributor.authorYang, ZJen_HK
dc.contributor.authorZhang, LRen_HK
dc.contributor.authorZhang, LHen_HK
dc.contributor.authorLeung, FPen_HK
dc.contributor.authorLam, CMCen_HK
dc.contributor.authorKwong, AKYen_HK
dc.contributor.authorYue, Jen_HK
dc.contributor.authorZhou, Yen_HK
dc.contributor.authorKriksunov, IAen_HK
dc.contributor.authorHao, Qen_HK
dc.contributor.authorCheung Lee, Hen_HK
dc.date.accessioned2011-08-26T14:26:30Z-
dc.date.available2011-08-26T14:26:30Z-
dc.date.issued2011en_HK
dc.identifier.citationOrganic And Biomolecular Chemistry, 2011, v. 9 n. 9, p. 3246-3257en_HK
dc.identifier.issn1477-0520en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137500-
dc.description.abstractHuman 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 (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. © 2011 The Royal Society of Chemistry.en_HK
dc.languageengen_US
dc.publisherRoyal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/obcen_HK
dc.relation.ispartofOrganic and Biomolecular Chemistryen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshAntigens, CD38 - antagonists and inhibitors - chemical synthesis - chemistry-
dc.subject.meshDrug Design-
dc.subject.meshGuinea Pigs-
dc.subject.meshModels, Molecular-
dc.subject.meshProtein Interaction Domains and Motifs-
dc.titleDesign, synthesis and biological characterization of novel inhibitors of CD38en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1477-0520&volume=9&issue=9&spage=3246&epage=3257&date=2011&atitle=Design,+synthesis+and+biological+characterization+of+novel+inhibitors+of+CD38en_US
dc.identifier.emailYue, J: jyue@hku.hken_HK
dc.identifier.emailHao, Q: qhao@hku.hken_HK
dc.identifier.authorityYue, J=rp00286en_HK
dc.identifier.authorityHao, Q=rp01332en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1039/c0ob00768den_HK
dc.identifier.pmid21431168-
dc.identifier.scopuseid_2-s2.0-79954431421en_HK
dc.identifier.hkuros191537en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79954431421&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume9en_HK
dc.identifier.issue9en_HK
dc.identifier.spage3246en_HK
dc.identifier.epage3257en_HK
dc.identifier.isiWOS:000289488000024-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38-
dc.identifier.scopusauthoridDong, M=36571659600en_HK
dc.identifier.scopusauthoridSi, YQ=49561826000en_HK
dc.identifier.scopusauthoridSun, SY=36106306500en_HK
dc.identifier.scopusauthoridPu, XP=7006161096en_HK
dc.identifier.scopusauthoridYang, ZJ=36112472600en_HK
dc.identifier.scopusauthoridZhang, LR=36109448800en_HK
dc.identifier.scopusauthoridZhang, LH=15040200600en_HK
dc.identifier.scopusauthoridLeung, FP=8615375300en_HK
dc.identifier.scopusauthoridLam, CMC=26026006700en_HK
dc.identifier.scopusauthoridKwong, AKY=54932929500en_HK
dc.identifier.scopusauthoridYue, J=7101875828en_HK
dc.identifier.scopusauthoridZhou, Y=49562143100en_HK
dc.identifier.scopusauthoridKriksunov, IA=6507909504en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK
dc.identifier.scopusauthoridCheung Lee, H=6504213639en_HK

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