2. Academic Validation
  3. Anthraquinones from Cassiae semen as thrombin inhibitors: in vitro and in silico studies

Anthraquinones from Cassiae semen as thrombin inhibitors: in vitro and in silico studies

  • Phytochemistry. 2019 Sep;165:112025. doi: 10.1016/j.phytochem.2019.04.018.
Xiao Yu 1,  Ling-Hua Wei 1,  Jia-Kai Zhang 1,  Tian-Ran Chen 1,  Qiang Jin 2,  Yi-Nan Wang 2,  Shui-Jun Zhang 1,  Tong-Yi Dou 3,  Yun-Feng Cao 4,  Wen-Zhi Guo 5,  Guang-Bo Ge 6,  Ling Yang 2
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University; Henan Key Laboratory of Digestive Organ Transplantation; Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities; Zhengzhou, 450001, China.
  • 2 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3 School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, China.
  • 4 Dalian Runsheng Kangtai Medical Laboratory Co.Ltd, Dalian, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University; Henan Key Laboratory of Digestive Organ Transplantation; Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities; Zhengzhou, 450001, China. Electronic address: guowz66@163.com.
  • 6 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: geguangbo@dicp.ac.cn.
PMID: 31207449 DOI: 10.1016/j.phytochem.2019.04.018
Abstract

Thrombin Inhibitor therapy is one of the most effective therapeutic strategies for the prevention and treatment of cardiovascular and thrombotic diseases. Although several marketed direct Thrombin inhibitors (DTIs) have been widely used in clinic, the potentially serious complications of these DTIs prompted the researchers to find more DTIs with improved safety profiles. Herein, we report that natural Anthraquinones in Cassiae semen (the seed of Cassia obtusifolia L. or C. tora L.), including obtusifolin, obtusin, aurantio-obtusin and chryso-obtusin, display strong to moderate inhibition on human Thrombin, with the IC50 values ranging from 9.08 μM to 27.88 μM. Further investigation on the inhibition kinetics demonstrates that these Anthraquinones are mixed inhibitors against thrombin-mediated Z-GGRAMC acetate hydrolysis, while obtusifolin and aurantio-obtusin show strong Thrombin inhibition capacity, with the Ki values of 9.63 μM and 10.30 μM, respectively. Docking simulations demonstrate that both obtusifolin and aurantio-obtusin can simultaneously bind on the catalytic cavity and the two anion binding exosites (ABE1 and ABE2), while the hydroxyl group at the C-7 site and the methoxyl group at the C-8 site can create key interactions with the Amino acids surrounding the catalytic cavity via hydrogen bonding. All these findings suggest that obtusifolin and aurantio-obtusin are strong Thrombin inhibitors possessing a unique anthraquinone skeleton, and could be used as lead compounds for the development of new Thrombin inhibitors with improved properties.

Keywords

Aurantio-obtusin; Cassia obtusifolia L.; Cassiae semen; Obtusifolin; Thrombin inhibitor.

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