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Int. J. Mol. Sci. 2018, 19(1), 77;

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea
Author to whom correspondence should be addressed.
Received: 21 October 2017 / Revised: 14 December 2017 / Accepted: 26 December 2017 / Published: 28 December 2017
(This article belongs to the Section Bioactives and Nutraceuticals)
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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. View Full-Text
Keywords: cheminformatics; docking simulation; drug repositioning; thiopurine; tyrosinase cheminformatics; docking simulation; drug repositioning; thiopurine; tyrosinase

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Choi, J.; Lee, Y.-M.; Jee, J.-G. Thiopurine Drugs Repositioned as Tyrosinase Inhibitors. Int. J. Mol. Sci. 2018, 19, 77.

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