Analyzing the potential of selected plant extracts and their structurally diverse secondary metabolites for α-glucosidase inhibitory activity: in vitro and in silico approach

Inhibiting alpha-glucosidase activity is a therapeutic method to regulate post-prandial hyperglycemia in humans. Here, in-vitro and in-silico studies were used to find alpha-glucosidase inhibitory plant secondary metabolites (PSM). Among 408 solvent extracts from 70 plants tested for alpha-glucosidase inhibition, 174 had IC50 <= 3 mg/ml. alpha-glucosidase inhibitory PSM is found in several plant species and solvent extracts, indicating their diversity. Further, ensemble molecular docking and structural activity relationship analysis supported this hypothesis where the top 100 PSM with the least binding energy (BE) among the 539 PSM belonged to sesquiterpenoids (34%), catechols (11%), flavonoids (9%) and steroidal lactones (8%). Shortlisted 11 PSM were subjected to molecular dynamic simulation. Withanolide J recorded the least BE of -66.424 +/- 22.333 kJ/mol, followed by Withacoagulin I (-64.665 +/- 24.030 kJ/mol). When different simulation frames were analyzed, PSM of withanolide groups was stabilized in the narrow entrance of the active pocket forming H-bond with LYS156, TYR158, PHE159, PHE303 PRO312, LEU313, ARG315 and PHE134. Similarly, Hydroxytuberosone and 1, 8-Dihydroxy-3-carboxy-9, 10-anthraquinone (DHCA) formed H-bond with ASP307 located on the loop at the entrance of the active pocket. In the case of Neoliquiritin and Kaempferol-3-o-alpha-L-rhamnoside (KALR), glucose moiety interacted with the GLU277 and ASP215 (catalytic amino acid residues) through H-bonds. In addition, these 11 PSM were found to fulfil the criteria of drug-likeness as per Lipinski's rule of five and pharmacokinetic profile. The present study strengthens the library of alpha-glucosidase inhibitory plants and PSM, providing valuable information for Type-II Diabetes mellitus management. Communicated by Ramaswamy H. Sarma