Tetrahydrobisbenzylisoquinoline alkaloids from Phaeanthus ophthalmicus inhibit target enzymes associated with type 2 diabetes and obesity

Abstract

Diabetes and obesity are metabolic comorbidities declared by WHO as epidemics. Owing to the purported pharmaceutical activities of plant-derived secondary metabolites, we assessed the inhibitory potentials of the Philippine native plant Phaeanthus ophthalmicus tetrahydrobisbenzylisoquinoline alkaloidal constituents tetrandrine ( 1 ) and limacusine ( 2 ) against enzymes implicated in type 2 diabetes (T2D) and obesity such as α-glucosidase, dipeptidyl peptidase-IV (DPP-IV), porcine pancreatic lipase (PPL), and human monoacylglycerol lipase (MAGL) using in vitro experiments and molecular docking. Both alkaloids 1 (IC50 = 2.29 μg/ml) and 2 (IC50 = 2.68 μg/ml) showed stronger inhibition against α-glucosidase compared to the drug control acarbose (IC50 = 4.12 μg/ml). Alkaloids 1 (IC50 = 4.92 μg/ml) and 2 (IC50 = 3.80 μg/ml) also exhibited better inhibitory activities against DPP-IV compared to the drug control sitagliptin (IC50 = 6.90 μg/ml). Molecular docking results revealed better binding propensities for both 1 and 2 onto the active pocket of α-glucosidase and DPP-IV compared to their respective control drugs. Meanwhile, alkaloid 2 showed better in vitro (IC 50 = 0.70 μg/ml) and in silico inhibitory activity vs PPL compared to orlistat. Both alkaloids 1 and 2 showed moderate bioactivity against MAGL. Both alkaloids were predicted to possess drug-likeness properties. Our present study suggests the potentials of the tetrahydrobisbenzylisoquinoline alkaloidal phytoconstituents tetrandrine ( 1 ) and limacusine ( 2 ) from P. ophthalmicus in developing new-generation prodrugs against T2D and obesity.