Inhibition of mushroom tyrosinase by a newly synthesized ligand: inhibition kinetics and computational simulations.
Alterations in the synthesis of melanin contribute to a number of diseases; therefore, the design of new tyrosinase inhibitors is very important. Mushroom tyrosinase (MT) is a metalloenzyme, which plays an important role in melanin biosynthesis. In this study, the inhibitory effect of a novel designed compound, i.e. 2-((1Z)-(2-(2,4-dinitrophenyl)hydrazin-1-ylidene)methyl)phenol, as a specific ligand which can bind to the copper ion of MT, has been assessed. The ligand was found to competitively inhibit both the cresolase and catecholase activities of MT, with small inhibition constants of 2.8 and 2.6 μM, respectively. Intrinsic fluorescence studies were performed to gain more information on the binding constants. Docking results indicated that the ligand binds to copper ions in the active site of MT via the OH group of the ligand. The ligand makes four hydrogen bonds with aspartic acid and one hydrogen bond with the histidine residue in the active site. Molecular dynamics results show that ligand binds to the MT via both electrostatic and hydrophobic interactions with its different parts.
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Mahdi
M
Alijanianzadeh
Ali Akbar
AA
Saboury
Mohammad Reza
MR
Ganjali
Hamid
H
Hadi-Alijanvand
Ali Akbar
AA
Moosavi-Movahedi
D000363:Agaricales / Q000737:chemistry / Q000201:enzymology; D001224:Aspartic Acid / Q000737:chemistry; D020134:Catalytic Domain; D004156:Catechol Oxidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006639:Histidine / Q000737:chemistry; D006835:Hydrazones / Q000138:chemical synthesis*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009578:Nitrobenzenes / Q000138:chemical synthesis*; D011485:Protein Binding; D013050:Spectrometry, Fluorescence
C576611:2-((2-(2,4-dinitrophenyl)hydrazin-1-ylidene)methyl)phenol; D004791:Enzyme Inhibitors; D006835:Hydrazones; D008024:Ligands; D009578:Nitrobenzenes; D001224:Aspartic Acid; D006639:Histidine; D003300:Copper; D004156:Catechol Oxidase; D014442:Monophenol Monooxygenase