title: Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening.
abstract: 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.
authors.affiliation: Beijing Key Lab of Traditional Chinese Medicine (TCM) Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China. wangxing@ccmu.edu.cn.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China. zhangyuxinwjzy@163.com.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China. sdliuqing17@tom.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Beijing Key Lab of Traditional Chinese Medicine (TCM) Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China. azxccmu@163.com.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Ai
authors.affiliation: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China. collean_zhang@163.com.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing 100069, China. cnuxiangyh@163.com.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China. yjqiao@bucm.edu.cn.
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Qiao
mesh_terms: D034341:Aristolochic Acids / Q000494:pharmacology*; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D010946:Plants, Medicinal / Q000737:chemistry*; D044022:Receptor, Endothelin A / Q000187:drug effects*; D044023:Receptor, Endothelin B / Q000187:drug effects*
chemical_list: D034341:Aristolochic Acids; C000588596:EDNRB protein, human; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C000228:aristolochic acid I
keywords: aristolochic acid A; bioassay evaluation; dual ETA/ETB receptor; molecular docking; pharmacophore