Phytochemical Profiling, Network Pharmacology, and Molecular Dynamics Simulations of Sinularia levi Metabolites as Potent α-Glucosidase Inhibitors in Metabolic Syndrome

Abstract

<title>Abstract</title> This study has investigated the phytochemical composition and therapeutic potential of the Red Sea soft coral <italic>Sinularia levi</italic> . Five compounds ( <bold>1–5</bold> ) comprising three glyceryl derivatives, a ceramide, and a diterpene were isolated and characterized. To elucidate their role in metabolic syndrome, an integrated network pharmacology and structure-based modelling workflow was employed. This approach identified 45 shared targets between <italic>S. levi</italic> metabolites and disease proteins, clustered into inflammatory and metabolic nodes, with α-glucosidase (GAA) emerging as a primary target. Molecular docking against GAA (PDB: 5NN8) identified glyceryl nonacosanol ( <bold>2</bold> ) as the most potent ligand (–8.5 kcal/mol), stabilized by a unique glycerol-head polar clamp involving Glu139 and Lys137. The stability of this complex was confirmed through a 100-ns MD simulation, which demonstrated sustained equilibrium and persistent hydrogen bonding. <italic>In vitro</italic> assays revealed that the total extract possesses significant antioxidant activity (DPPH IC ₅₀ ​ = 18.66 µg/mL), the isolated compounds exhibited selective enzyme inhibition. In which, Glyceryl nonacosanol ( <bold>2</bold> ) proved to be the most effective α-glucosidase inhibitor (IC ₅₀ ​=326.77 µg/mL), whereas glyceryl pentacosanoate ( <bold>5</bold> ) showed the highest activity against pancreatic lipase (IC ₅₀ ​= 170.75 µg/mL). These findings suggest that <italic>S. levi</italic> metabolites, particularly glyceryl nonacosanol, represent promising leads for managing postprandial glucose levels.