The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation
Xu, Guowei1,2,3; Yang, Yaqing4,5; Yang, Yanming4,5; Song, Gao4,5; Li, Shanshan4,5; Zhang, Jiajun4,5; Yang, Weimin4,5; Wang, Liang-Liang1,2,3; Weng, Zhiying4,5; Zuo, Zhili1,2,3
Corresponding AuthorWang, Liang-Liang(wangliangliang@mail.kib.ac.cn) ; Weng, Zhiying(weng_zy@sina.com) ; Zuo, Zhili(zuozhili@mail.kib.ac.cn)
2020-04-01
Source PublicationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN0223-5234
Volume191Pages:11
AbstractAdenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 mu M on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2. (c) 2020 Elsevier Masson SAS. All rights reserved.
KeywordAdenylate cyclase Agonist Virtual screening Cyclic adenosine monophosphate Interleukin-6
DOI10.1016/j.ejmech.2020.112115
Indexed BySCI ; SCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000523562700024
Citation statistics
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/71493
Collection植物化学与西部植物资源持续利用国家重点实验室
Corresponding AuthorWang, Liang-Liang; Weng, Zhiying; Zuo, Zhili
Affiliation1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
2.Yunnan Key Lab Nat Med Chem, Kunming 650201, Yunnan, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Kunming Med Univ, Sch Pharmaceut Sci, Kunming 650500, Yunnan, Peoples R China
5.Kunming Med Univ, Yunnan Key Lab Pharmacol Nat Prod, Kunming 650500, Yunnan, Peoples R China
Recommended Citation
GB/T 7714
Xu, Guowei,Yang, Yaqing,Yang, Yanming,et al. The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,191:11.
APA Xu, Guowei.,Yang, Yaqing.,Yang, Yanming.,Song, Gao.,Li, Shanshan.,...&Zuo, Zhili.(2020).The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,191,11.
MLA Xu, Guowei,et al."The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 191(2020):11.
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