Discovery of Diosgenin as Potent and Selective Inhibitors Against Human Carboxylesterase 2
Xiao-Dong Li1,2,a, Hong-Hong Ma2,a, Jun-Qing Gao1, Yi-Shu Zhao2, Xing-Kai Qian2, Guang-Bo Ge2, Li-Wei Zou2,a*, Zong-Jun Liu1,a* and Ling Yang2
1Department of Cardiology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
aThese Authors have Contributed Equally to this Work
*Corresponding Author: Li-Wei Zou, Institute of Interdisciplinary Integrative Medicine
Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China and
Zong-Jun Liu, Department of Cardiology, Putuo Hospital, Shanghai University of Traditional
Chinese Medicine, Shanghai, China.
November 02, 2021; Published: November 18, 2021
Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz. has the effects of clearing away heat and toxin, relieving swelling and pain, cooling the liver, and calming convulsion. Human carboxylesterase 2 (hCES2A), one of the most principal drug-metabolizing enzymes, catalyzes the hydrolysis of a variety of endogenous esters and environmental toxicants. In this study, the inhibitory effects against hCES2A of four active ingredients of Paris Polyphylla were assayed using diacetylfluorescein (FD) as a specific optical substrate for hCES2A. Among the four compounds, diosgenin displayed significantly inhibitory activity against hCES2A. Further investigations demonstrate that diosgenin exhibits strong hCES2A inhibition selectivity over other human serine hydrolases, including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE), pancreatic lipase (PL), and thrombin. According to its inhibition kinetic result, diosgenin was a mixed model type inhibitor, and Ki was 1.15 μM. Molecular docking showed that diosgenin could dock well to the active site and Z site of hCES2A, and the hydrophobic interactions might be the major ways for the binding of diosgenin on hCES2A. All results indicated that diosgenin is a potent and selective hCES2A inhibitor, which may potentially affect the metabolism of endogenous substances or cause unpredictable DDI by inhibiting the activity of hCES2A.
Keywords : Paris Polyphylla; Diosgenin; Human Carboxylesterase 2; Inhibitor; Molecular Docking Simulations
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