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  3. The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation

The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation

  • Eur J Med Chem. 2020 Apr 1;191:112115. doi: 10.1016/j.ejmech.2020.112115.
Guowei Xu 1,  Yaqing Yang 2,  Yanming Yang 2,  Gao Song 2,  Shanshan Li 2,  Jiajun Zhang 2,  Weimin Yang 2,  Liang-Liang Wang 3,  Zhiying Weng 4,  Zhili Zuo 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 2 School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, Yunnan, China.
  • 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: wangliangliang@mail.kib.ac.cn.
  • 4 School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, Yunnan, China. Electronic address: weng_zy@sina.com.
  • 5 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: zuozhili@mail.kib.ac.cn.
PMID: 32105982 DOI: 10.1016/j.ejmech.2020.112115
Abstract

Adenylate 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 μM 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.

Keywords

Adenylate cyclase; Agonist; Cyclic adenosine monophosphate; Interleukin-6; Virtual screening.

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