Abstract
Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.
Highlights
The colour of the human skin is predominantly determined by the amount of melanin that is produced in the skin melanocytes
The reproduced poses of phenylthiourea and tropolone were compared with those that were found in the crystal structures, leading to the selection of DOCK 3.6 [32] as the docking algorithm among four software
Dockings with the molecular dynamics simulation-derived ensemble using a mixture of known ligands and their physicochemically matched, but topologically different, decoys led to the selection of the best structure based on the metrics from the receiver operating characteristic (ROC) curve
Summary
The colour of the human skin is predominantly determined by the amount of melanin that is produced in the skin melanocytes. The cognate substrate, tyrosine, is converted into dihydroxyphenylalanine (DOPA) and subsequently into dopaquinone by tyrosinase, and spontaneously into melanin via eumelanin. Tyrosinase, catechol oxidase, and haemocyanin are type-3 copper proteins, which possess two juxtaposed copper ions in the catalytic centre. In the hydroxylation of monophenol to diphenol, and its subsequent conversion to quinone by tyrosinase, catechol oxidase only catalyses the second oxidation. The primary role of haemocyanin in some invertebrates is the carriage of oxygen. The copper ions of tyrosinase interchange among four oxidation states (oxy-, met-, deoxy-, and deact-) [1]. The catalytic activity is coupled to the cycle, providing the substrates with molecular oxygen
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