فهرست نشریات علمی دسترسی آزاد ایران

Pigmentation disorders are often associated with dysregulation of the Frizzled signaling pathway. Natural metabolites from the mangrove species Rhizophora mucronata have been reported to contain bioactive compounds with therapeutic potential. However, their role as modulators of Frizzled receptors remains largely unexplored. In this study, an integrated computational approach was employed, encompassing metabolite profiling, homology modeling, molecular docking, and molecular dynamics simulations. Metabolite profiling of R. mucronata root and stem bark extracts identified 93 and 63 compounds, respectively, from which 29 and 19 compounds were selected based on match score and relevance. A homologous model of the Frizzled-3 (FZD3) receptor was constructed and validated using Ramachandran plot analysis. Molecular docking and MMGBSA analyses identified six key metabolites catechin, phloretin, glycerophosphoglycerol, caffeic acid, coniferyl alcohol, and 3-methoxy-4-hydroxyphenylethyleneglycol sulfate as potential FZD3 modulators. Among them, catechin exhibited the most favorable binding free energy (-56.27 kcal/mol), followed by phloretin (-53.99 kcal/mol), glycerophosphoglycerol (-52.40 kcal/mol), caffeic acid (-46.11 kcal/mol), and 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (-45.61 kcal/mol), whereas MHPG showed the least favorable binding (-36.44 kcal/mol). Molecular dynamics simulations confirmed complex stability through minimal RMSD fluctuations, consistent Rg values, and persistently negative MMGBSA energies. Specifically, caffeic acid and phloretin maintained stable hydrogen bonding and hydrophobic interactions within the FZD3 binding pocket, suggesting their potential role in modulating receptor conformation and signaling. Overall, this study highlights R. mucronata root and stem bark metabolites as promising natural modulators of Frizzled receptors, particularly FZD3, which plays a crucial role in pigmentation regulation. These findings provide a solid computational foundation for future in vitro and in vivo validation, supporting the potential of mangrove-derived compounds in the development of targeted pigmentation therapies.