A Repurposing Pipeline to Candidate‐Suitable Inhibitors of Tyrosinase: Computational and Bioassay Studies

Abstract Tyrosinase, a metalloprotein enzyme, plays a crucial role in melanin synthesis by hydroxylating L‐tyrosine to L‐dopa. However, the accumulation of melanin can lead to hyperpigmented spots, raising aesthetic concerns. In this study, we developed a pipeline to repurpose FDA‐approved drugs as potential tyrosinase inhibitors. A structure‐based screening study was conducted using 1,650 drugs to identify probable inhibitors based on binding energies. From the cluster analysis of binding interaction profiles, 16 compounds were selected as candidates. Montelukast emerged as the final candidate due to its favorable ADME properties. Bioassay evaluation revealed an IC50 value of 14.79±0.87 μM for Montelukast, compared to kojic acid (IC50=31.02±2.01 μM). Molecular dynamics simulation and g_MMPBSA free energy calculation studies were performed for the Tyrosinase‐Montelukast complex. These findings enhance our understanding of Tyrosinase‐Montelukast interactions and underscore Montelukast's potential as a tyrosinase inhibitor. This could have implications in dermatological applications and beyond, suggesting Montelukast as a promising candidate for further development in this regard.