Kabiri Maryam, Hajizade Mohammad Soroosh, Zarei Mina, Eskandari Simin, Sakhteman Amirhossein, Khoshneviszadeh Mehdi
College of Graduate Studies, Upstate Medical University, State University of New York, USA.
Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Science, PO Box 71345-3388, Shiraz, Iran.
Chem Biodivers. 2024 Dec;21(12):e202401035. doi: 10.1002/cbdv.202401035. Epub 2024 Oct 18.
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.
酪氨酸酶是一种金属蛋白酶，通过将L-酪氨酸羟基化为L-多巴，在黑色素合成中发挥关键作用。然而，黑色素的积累会导致色素沉着斑，引发美学问题。在本研究中，我们开发了一种流程，将美国食品药品监督管理局（FDA）批准的药物重新用作潜在的酪氨酸酶抑制剂。使用1650种药物进行了基于结构的筛选研究，以根据结合能确定可能的抑制剂。通过对结合相互作用谱的聚类分析，选择了16种化合物作为候选物。孟鲁司特因其良好的药代动力学和药效学性质而成为最终候选物。生物测定评估显示，孟鲁司特的IC50值为14.79±0.87 μM，而曲酸的IC50值为31.02±2.01 μM。对酪氨酸酶-孟鲁司特复合物进行了分子动力学模拟和g_MMPBSA自由能计算研究。这些发现加深了我们对酪氨酸酶-孟鲁司特相互作用的理解，并强调了孟鲁司特作为酪氨酸酶抑制剂的潜力。这可能在皮肤病学及其他领域有应用，表明孟鲁司特是这方面进一步开发的有前景的候选物。
