Three naturally occurring prenylated pyranocoumarins, nordentatin (1), dentatin (2), and clausarin (3), isolated from the roots of Clausena excavata (Family Rutaceae), and O-methylclausarin (4) which was obtained by methylation of 3, were investigated for their α-glucosidase inhibitory activity. The mechanism of action and the in silico prediction of their physicochemical and ADMET properties as well as the molecular docking were also studied. Compounds 1-4 exhibited stronger α-glucosidase inhibitory activity than the positive control, acarbose, through a non-competitive mechanism. Among them, 3 exhibited the highest activity, with an IC50 of 8.36 μM, which is significantly stronger than that of acarbose (IC50=430.35 μM). The prenyl group on C-3 and the hydroxyl group on C-5 in 3 may play important roles in enhancing the activity. Calculated physicochemical and ADMET parameters of 1-4 satisfied the Lipinski's and Veber's rules. Molecular simulation analysis indicated they are promising drug candidates with no hepatotoxicity. Compound 3 exhibited potent activity in the experiment and demonstrated good drug properties based on the calculations. A molecular docking study revealed that 3 showed H-bonding and π-π stacking interactions with selective Phe321, as well as interactions with thirteen other amino acid residues of the α-glucosidase.
Keywords: ADMET; Clausena excavata; Molecular docking; Pyranocoumarins; α-Glucosidase inhibition.
© 2024 Wiley-VHCA AG, Zurich, Switzerland.