2. Academic Validation
  3. Discovery of a highly specific and efficacious inhibitor of human carboxylesterase 2 by large-scale screening

Discovery of a highly specific and efficacious inhibitor of human carboxylesterase 2 by large-scale screening

  • Int J Biol Macromol. 2019 Sep 15;137:261-269. doi: 10.1016/j.ijbiomac.2019.06.235.
Yun-Qing Song 1,  Xiao-Qing Guan 1,  Zi-Miao Weng 2,  Ya-Qiao Wang 1,  Jing Chen 3,  Qiang Jin 1,  Sheng-Quan Fang 4,  Bin Fan 4,  Yun-Feng Cao 5,  Jie Hou 6,  Guang-Bo Ge 7
Affiliations

Affiliations

  • 1 Translational Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine & Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 200473, China.
  • 2 Translational Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine & Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 200473, China; Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
  • 3 School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China.
  • 4 Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
  • 5 Key Laboratory of Contraceptives and Devices Research, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China.
  • 6 Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China. Electronic address: [email protected].
  • 7 Translational Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine & Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 200473, China. Electronic address: [email protected].
PMID: 31260759 DOI: 10.1016/j.ijbiomac.2019.06.235
Abstract

Human carboxylesterase 2 (CES2A), one of the most abundant hydrolases distributed in human small intestine and colon, play key roles in the hydrolysis of a wide range of prodrugs and other esters. Recent studies have demonstrated that CES2A inhibitors may ameliorate irinotecan-induced severe diarrhea, but the specific and efficacious inhibitors targeting intracellular CES2A are rarely reported. Herein, a large-scale screening campaign was conducted for discovery of potent and specific CES2A inhibitor(s). Following screening of more than one hundred of Natural Products, glabridin (a bioactive compound of Glycyrrhiza glabra L.) was found displaying potent inhibition on CES2A and high specificity over CES1A (>500-fold) and other serine hydrolases. Further investigation showed that glabridin was cell permeable and low cytotoxic, as well as capable of inhibiting intracellular CES2A in living cells, with the IC50 value of 0.52 μM. Molecular dynamics simulations showed that glabridin formed strong and stable interactions with both the catalytic cavity and Z site of CES2A via hydrophobic interactions. In summary, glabridin was a potent and specific inhibitor targeting intracellular CES2A, which could be used as an ideal lead compound to develop more efficacious CES2A inhibitors for modulating the pharmacokinetic behaviors of CES2A-substrate drugs and alleviating irinotecan-induced diarrhea.

Keywords

Glabridin; Human carboxylesterase 2 (CES2A); Inhibition mechanism; Irinotecan-induced diarrhea; Specific inhibitor.

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