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Int. J. Mol. Sci. 2016, 17(3), 389; doi:10.3390/ijms17030389

Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

Beijing Key Lab of Traditional Chinese Medicine (TCM) Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
Department of Chemistry, Capital Normal University, Beijing 100069, China
Author to whom correspondence should be addressed.
Academic Editors: Ge Zhang and Aiping Lu
Received: 23 January 2016 / Revised: 25 February 2016 / Accepted: 4 March 2016 / Published: 16 March 2016
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Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA. View Full-Text
Keywords: dual ETA/ETB receptor; pharmacophore; molecular docking; aristolochic acid A; bioassay evaluation dual ETA/ETB receptor; pharmacophore; molecular docking; aristolochic acid A; bioassay evaluation

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Wang, X.; Zhang, Y.; Liu, Q.; Ai, Z.; Zhang, Y.; Xiang, Y.; Qiao, Y. Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening. Int. J. Mol. Sci. 2016, 17, 389.

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