title: Structure-activity relationships of the thujaplicins for inhibition of human tyrosinase.
abstract: Tyrosinase inhibitors have become increasingly critical agents in cosmetic, agricultural, and medicinal products. Although a large number of tyrosinase inhibitors have been reported, almost all the inhibitors were unfortunately evaluated by using commercial available mushroom tyrosinase. Here, we examined the inhibitory effects of three isomers of thujaplicin (α, β, and γ) on human tyrosinase and analyzed their binding modes using homology model and docking studies. As the results, γ-thujaplicin was found to strongly inhibit human tyrosinase with the IC50 of 1.15 μM, extremely superior to a well-known tyrosinase inhibitor kojic acid (IC50 = 571.17 μM). MM-GB/SA binding free energy decomposition analyses suggested that the potent inhibitory activity of γ-thujaplicin may be due to the interactions with His367, Ile368, and Val377 (hot spot amino acid residues) in human tyrosinase. Furthermore, the binding mode of α-thujaplicin indicated that Val377 and Ser380 may cause van der Waals clashes with the isopropyl group of α-thujaplicin. These results provide a novel structural insight into the hot spot of human tyrosinase for the specific binding of γ-thujaplicin and a way to optimize not only thujaplicins but also other lead compounds as specific inhibitors for human tyrosinase in a rational manner.
authors.affiliation: Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama 226-8510, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshimori
authors.affiliation: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama 226-8510, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kamiya
authors.affiliation: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan; Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan. Electronic address: tanuma@rs.noda.tus.ac.jp.
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Tanuma
mesh_terms: D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C116333:2-hydroxy-5-isopropyl- 2,4,6-cycloheptatrienone; D004791:Enzyme Inhibitors; D039821:Monoterpenes; C556010:alpha-thujaplicin; D014334:Tropolone; D014442:Monophenol Monooxygenase; C009479:beta-thujaplicin
keywords: Free energy decomposition analysis; Homology modeling; Hot spot; Human tyrosinase; MM-GB/SA; Thujaplicins