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
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虚拟筛选结合生物学评价发现、设计和合成2型腺苷酸环化酶强效激动剂
DOI：
10.1016/j.ejmech.2020.112115
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发表时间：
2020
影响因子：
6.7
通讯作者：
Zhili Zuo
中科院分区：
文献类型：
--
作者：
Guowei Xu;Yaqing Yang;Yanming Yang;Gao Song;Shanshan Li;Jiajun Zhang;Weimin Yang;Liang-Liang Wang;Zhiying Weng;Zhili Zuo
腺苷环化酶(Acs)在三磷酸腺苷(ATP)转化为第二信使环磷酸腺苷(CAMP)的过程中起着关键作用。研究表明，腺酰环化酶2(Ac2)是治疗多种疾病的潜在药物靶点，但目前尚无AC2选择性激动剂的报道。在这项研究中，基于对接的虚拟筛选和基于细胞的生物检测相结合，已经被用来发现新的有效和选择性的AC2激动剂。虚拟筛选揭示了一种新的HIT化合物8作为AC2激动剂，其对重组人hAC2+HEK293细胞的EC50值为8.10μM。在重组AC2细胞上进一步研究了化合物8衍生物的构效关系，发现化合物73是最具活性的激动剂，其EC50为90 nM，是已报道的激动剂Forsklin的160倍，并能选择性地激活AC2以抑制IL-6的表达。新型AC2选择性激动剂的发现将为研究AC2的生理功能提供一种新的化学探针。
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 compound8as an AC2 agonist with EC50value of 8.10 μM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound8was further explored on recombinant AC2 cells and compound73was found to be the most active agonist with the EC50of 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.