Insights into in vitro and in silico studies of α-glucosidase inhibitors isolated from the leaves of Grewia optiva (Malvaceae)

α-Glucosidase plays a critical role in glucose metabolism by breaking down complex carbohydrates into simpler sugars for intestinal absorption. Due to the side effects of current α-glucosidase inhibitors, there is increasing interest in exploring alternative therapeutic options. Inspired by the traditional uses of Grewia optiva J.R.Drumm. ex Burret (Malvaceae family) as an anti-diabetic herb, we isolated gnaphaffine A (1), a cyclic glycosylated homolignan, together with kaempferol derivatives (trans-tiliroside 2, cis-tiliroside 3, and astragalin 4) from the ethyl acetate fraction. In vitro antioxidant assays revealed that 1 exhibited anti-DPPH• and anti-ABTS+• activity (IC50 of 39.42 and 52.84 μg/mL, respectively), comparable to ascorbic acid (IC50 of 43.34 and 47.56 μg/mL, respectively). Moreover, 1 demonstrated a seven-fold stronger inhibition of α-glucosidase activity than acarbose (IC50 of 8.2 and 57.8 μg/mL, respectively). Importantly, 1 was non-toxic to AC16 normal cardiomyocyte cell lines. Computational analyses identified two key factors contributing to the α-glucosidase inhibitory activity of 1: (a) hydrogen bonding interactions with catalytic residues (E277 and D352) and (b) a calculated ∆Gbind of −51.20 kcal/mol. Furthermore, 3 showed the most favorable in silico binding profile, with the highest ∆Gbind (−55.89 kcal/mol) and higher hydrogen bond occupancy compared to 1 and 2. These findings suggest that 1 and 3 may serve as promising lead compounds for the development of new α-glucosidase drugs. [Display omitted]