title: A new insight into mushroom tyrosinase inhibitors: docking, pharmacophore-based virtual screening, and molecular modeling studies.
abstract: Tyrosinase, a widely spread enzyme in micro-organisms, animals, and plants, participates in two rate-limiting steps in melanin formation pathway which is responsible for skin protection against UV lights' harm whose functional deficiency result in serious dermatological diseases. This enzyme seems to be responsible for neuromelanin formation in human brain as well. In plants, the enzyme leads the browning pathway which is commonly observed in injured tissues that is economically very unfavorable. Among different types of tyrosinase, mushroom tyrosinase has the highest homology with the mammalian tyrosinase and the only commercial tyrosinase available. In this study, ligand-based pharmacophore drug discovery method was applied to rapidly identify mushroom tyrosinase enzyme inhibitors using virtual screening. The model pharmacophore of essential interactions was developed and refined studying already experimentally discovered potent inhibitors employing Docking analysis methodology. After pharmacophore virtual screening and binding modes prediction, 14 compounds from ZINC database were identified as potent inhibitors of mushroom tyrosinase which were classified into five groups according to their chemical structures. The inhibition behavior of the discovered compounds was further studied through Classical Molecular Dynamic Simulations and the conformational changes induced by the presence of the studied ligands were discussed and compared to those of the substrate, tyrosine. According to the obtained results, five novel leads are introduced to be further optimized or directly used as potent inhibitors of mushroom tyrosinase.
authors.affiliation: a Department of Medicinal Chemistry, Faculty of Pharmacy and Medicinal Plants Research Center , Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Kowsar
authors.initials: K
authors.lastname: Bagherzadeh
authors.forename: Faezeh
authors.initials: F
authors.lastname: Shirgahi Talari
authors.forename: Amirhossein
authors.initials: A
authors.lastname: Sharifi
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ganjali
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Saboury
authors.forename: Massoud
authors.initials: M
authors.lastname: Amanlou
mesh_terms: D000363:Agaricales / Q000201:enzymology; D020134:Catalytic Domain; D003300:Copper / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D014867:Water; D003300:Copper; D014442:Monophenol Monooxygenase
keywords: LigandScout; inhibitor; ligand-based pharmacophore; molecular dynamic simulations; mushroom tyrosinase; virtual screening