Phytochemical profiling, network pharmacology, and molecular dynamics simulations of Sinularia levi metabolites as potential α-glucosidase inhibitors in metabolic syndrome

Abstract

This study has investigated the phytochemical composition and therapeutic potential of the Red Sea soft coral Sinularia levi. Five compounds (1–5) 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 modeling workflow was employed. This approach identified 45 shared targets between S. levi 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 1-O-nonacosylglycerol (2) as the most potent ligand (−8.5 kcal mol−1), 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. In vitro assays revealed that the total extract possesses significant antioxidant activity (DPPH IC50 = 18.66 µg mL−1), and the isolated compounds exhibited selective enzyme inhibition. In which, 1-O-nonacosylglycerol (2) proved to be the most effective α-glucosidase inhibitor (IC50 = 326.77 µg mL−1), whereas glyceryl pentacosanoate (5) showed the highest activity against pancreatic lipase (IC50 = 170.75 µg mL−1). These findings suggest that S. levi metabolites, particularly 1-O-nonacosylglycerol, represent preliminary screening for managing postprandial glucose levels.