In silico and in vitro study for the limonoid isolated from Swietenia macrophylla as potential α-glucosidase inhibitor.

Limonoids are important constituents of Swietenia macrophylla, exhibiting a range of biological activities that influence human health. Swietenia macrophylla, a well-known medicinal plant, is particularly rich in limonoids, which have been reported to exhibit significant therapeutic potential. Given the increasing interest in natural α-glucosidase inhibitors as potential treatments for diabetes mellitus, this study aimed to isolate, characterize, and evaluate the inhibitory potential of a major limonoid from Swietenia macrophylla seeds. Followed by chromatographic separation of the methanol extract, the purified compound was characterized using high-performance liquid chromatography (HPLC), mass spectrometry (MS), and single-crystal X-ray diffraction. The isolated limonoid, identified as swietenolide, exhibited a molecular weight of 486.20 g/mol and was crystallized in the P21 space group. Hirshfeld surface analysis revealed key intermolecular interactions stabilizing the crystal structure. To evaluate the binding potential of the isolated limonoid against the α-glucosidase enzyme, in silico molecular docking studies were performed, followed by molecular dynamics simulations to assess the binding affinity and stability of the compound at the enzyme's active site. To gain deeper insights into the molecular recognition process, fluorescence quenching assay, and isothermal titration calorimetry were performed to investigate the binding events and conformational changes in the enzyme upon ligand binding. The present study provides structural, computational, and experimental studies supporting the role of swietenolide as a potential natural α-glucosidase inhibitor. The combination of crystallographic characterization, molecular docking, molecular dynamics simulation, MM-GBSA, and fluorescence spectroscopy highlights its potential as a promising compound for antidiabetic drug development.