In silico and in vitro studies on antidiabetic potential of Niacin ester derivative of Oleanolic acid

Background: Oleanolic acid (OA) has been found to exert bene?cial effects against Type 2 Diabetes mellitus and metabolic syndrome. This study aims at designing derivatives of OA and evaluating their binding affinities to protein targets implicated in diabetes. Synthesis, physicochemical and in vitro studies were carried out on one of the promising ligand – niacin derivative (ND). Method: Thirty derivatives of OA were designed with ChemDraw ultra. The eight targets implicated in diabetes include; ?-amylase (AAM); Protein Tyrosine Phosphatase 1B (PTP1B); Dipeptidyl peptidase (DPP4); ?-glucosidase (AGCS); Glycogen synthase kinases 3? (GSK3); Fructose-1,6-diphosphatase (F1,6DP); Peroxisome proliferator-activated receptor gamma (PPARG) and Glucokinase (GLK). These were downloaded from the Protein data bank. Ligands and targets were converted to pdbqt format using PyRx. Molecular docking was done using Autodock Vina. Discovery Studio was used to analyze ligand-protein binding interactions. Pharmacokinetic properties were calculated from pKCM website and molecular properties from molinspiration websites. Synthesis of ND was done base on acyl chloride nucleophilic substitution method. In vitro study was done using ?-amylase inhibition and glucose uptake by yeast cells methods. Results: In silico, Ligand 16 (ND) showed better binding activity on more than one target over OA. (AAM, DPP4, PPARG, PTB1B and GLK).  In vitro, the ?-amylase inhibition values for IC50; (Acarbose:48.21±0.56 ?g/mL, OA:26.40±0.32 ?g/mL; ND = 24.25±0.52). For % glucose uptake by yeast cells (OA=80.2; ND=88.5; Glibenclamide=72.6) Conclusion: Higher binding affinities, low IC50 and higher glucose uptake by yeast cells observed in niacin derivative ND show that it is a potential antidiabetic compound.