Biocomputational-mediated screening and molecular docking platforms for discovery of coumarin-derived antimelanogenesis agents

Background: Hyperpigmentation occurs when excess melanin accumulates in the skin and causes the skin to become darker in color. Pursuing attractive appearance and colorism have promoted the development of the skin whitening market globally. The proteins targeted in this research are tyrosinase-related protein 1, cyclic adenosine monophosphate response element-binding protein, receptor tyrosine kinase, and endothelin receptor type B. Objectives: This study aims to identify the potential of coumarin derivatives as novel effective, safe, and natural antimelanogenesis agents for whitening purposes or therapeutical intention to treat hyperpigmentation disorders. Methods: Four three-dimensional structures of the targeted proteins and 94 ligands were obtained from Protein Data Bank and PubChem, respectively. The ligands were docked against modified targeted proteins to examine the binding affinity and protein-ligand interactions using PyRx and BIOVIA Discovery Studio. The top 13 derivatives were selected for further analysis on the pharmacokinetic properties through SwissADME and pkCSM web servers. A total of eight compounds were further chosen to conduct multiple ligand simultaneous docking (MLSD). Results: Difenacoum is the most potential antimelanogenesis agent due to its strong inhibitory binding affinity in targeted protein models (5M8M, 4TQN, 5X93), but it does not exhibit favorable behavior pharmacokinetic properties. From the in silico pharmacokinetics screening, novobiocin sodium is the most potent derivative due to its relatively appropriate and safer properties. However, none of the ligand pairs investigated in MLSD possesses a synergistic effect on the binding affinity. Conclusion: Our findings identified colladin, farnesiferol C and novobiocin sodium may be promising natural resources for developing antimelanogenesis agents.