Discovery of amphotericin B, an antifungal drug as tyrosinase inhibitor with potent anti-melanogenic activity

Tyrosinase, a rate-limiting enzyme for melanin production, has been the most efficient target for the development of depigmenting agents. Although hydroquinone, kojic acid, and arbutin are the most well-known tyrosinase inhibitors, their adverse effects are inevitable. In the present study, an in silico drug repositioning combined with experimental validation was performed to search for novel potent tyrosinase inhibitors. Docking-based virtual screening results revealed that, among the 3210 FDA-approved drugs available in the ZINC database, amphotericin B, an antifungal drug exhibited the highest binding efficiency against human tyrosinase. Results from tyrosinase inhibition assay demonstrated that amphotericin B could inhibit the activity of mushroom and cellular tyrosinases, especially from MNT-1 human melanoma cells. Molecular modeling results revealed that amphotericin B/human tyrosinase complex exhibited high stability in an aqueous environment. Melanin assay results demonstrated that amphotericin B significantly suppressed melanin production in α-MSH-induced B16F10 murine melanoma and MNT-1 human melanoma cell lines better than the known inhibitor, kojic acid. Mechanistically, amphotericin B treatment significantly activated ERK and Akt signaling pathways, resulting in the decreased expression of MITF and tyrosinase. The obtained results may pursue pre-clinical and clinical studies to examine the possibility of using amphotericin B as an alternative treatment for hyperpigmentation disorders.