title: Highly potent tyrosinase inhibitor, neorauflavane from Campylotropis hirtella and inhibitory mechanism with molecular docking.
abstract: Tyrosinase inhibition may be a means to alleviate not only skin hyperpigmentation but also neurodegeneration associated with Parkinson's disease. In the course of metabolite analysis from tyrosinase inhibitory methanol extract (80% inhibition at 20 μg/ml) of Campylotropis hirtella, we isolated fourteen phenolic compounds, among which neorauflavane 3 emerged as a lead structure for tyrosinase inhibition. Neorauflavane 3 inhibited tyrosinase monophenolase activity with an IC50 of 30 nM. Thus this compound is 400-fold more active than kojic acid. It also inhibited diphenolase (IC50=500 nM), significantly. Another potent inhibitor 1 (IC50=2.9 μM) was found to be the most abundant metabolite in C. hirtella. In kinetic studies, compounds 3 showed competitive inhibitory behavior against both monophenolase and diphenolase. It manifested simple reversible slow-binding inhibition against monophenolase with the following kinetic parameters: Ki(app)=1.48 nM, k3=0.0033 nM(-1) min(-1) and k4=0.0049 min(-1). Neorauflavane 3 efficiently reduced melanin content in B16 melanoma cells with 12.95 μM of IC50. To develop a pharmacophore model, we explored the binding mode of neuroflavane 3 in the active site of tyrosinase. Docking results show that resorcinol motif of B-ring and methoxy group in A-ring play crucial roles in the binding the enzyme.
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Tan
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Yeong Hun
authors.initials: YH
authors.lastname: Song
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Chanin
authors.initials: C
authors.lastname: Park
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jeong Yoon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Dae Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Kwang Dong
authors.initials: KD
authors.lastname: Kim
authors.affiliation: Division of Applied Life Science (BK21 plus), PMBBRC, RINS, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Curtis-Long
authors.affiliation: Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 660-701, Republic of Korea. Electronic address: khpark@gnu.ac.kr.
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007887:Fabaceae / Q000737:chemistry*; D007529:Isoflavones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008543:Melanins / Q000096:biosynthesis; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007529:Isoflavones; D008543:Melanins; C000609881:neorauflavane; D014442:Monophenol Monooxygenase
keywords: Campylotropis hirtella; Competitive inhibitor; Molecular docking; Neorauflavane; Tyrosinase