title: In silico investigation of cycloartane triterpene derivatives from Cimicifuga dahurica (Turcz.) Maxim. roots for the development of potent soluble epoxide hydrolase inhibitors.
abstract: In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that an ethanolic extract of the roots of Cimicifuga dahurica (Turcz.) Maxim. significantly inhibits sEH in vitro. A phytochemical study on the dichloromethane fraction of C. dahurica resulted in the isolation of two new cycloartane triterpenoids (1 and 6), together with 13 known cycloartane analogues (2-5 and 7-15). The structures of compounds were determined by spectroscopic methods. All of the triterpenoid derivatives inhibited sEH enzymatic activity in a concentration-dependent manner, and 13 of the tested compounds showed significant activity. Among them, compounds 1, 3, 5, 7, 9, and 12 showed the highest levels of inhibitory activity, with IC50values of about 5μM or less. Kinetic analysis of compounds 1, 3, 5-9, 11, 12, and 14 revealed that compounds 3, 6, 7, 11, and 14 were non-competitive; 1, 5, 9, and 12 were mixed-type; and 8 was a competitive inhibitor. Furthermore, in silico molecular docking indicated that compounds 3, 6-9, 11, 12, and 14 bound to sEH in a similar manner and had stable binding energies, as calculated by AutoDock 4.2 and processed in a 10,000-ps molecular dynamics simulation to assess the binding stability of compounds 5, 7, and 9.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.
authors.forename: Nguyen Phuong
authors.initials: NP
authors.lastname: Thao
authors.affiliation: Korea Atomic Energy Research Institute, Jeongeup, Jeollabuk-do 580-185, Republic of Korea.
authors.forename: Jang Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Industry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Vietnam.
authors.forename: Bui Thi
authors.initials: BT
authors.lastname: Thuy Luyen
authors.affiliation: Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.
authors.forename: Nguyen Tien
authors.initials: NT
authors.lastname: Dat
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: yhk@cnu.ac.kr.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
mesh_terms: D031885:Cimicifuga / Q000737:chemistry*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018517:Plant Roots / Q000737:chemistry*; D000072417:Protein Domains; D012995:Solubility; D014315:Triterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014315:Triterpenes; C085352:cycloartane; D004851:Epoxide Hydrolases
keywords: Cimicifuga dahurica; Cycloartane-type triterpenoids; Molecular docking; Ranunculaceae; Soluble epoxide hydrolase