Molecular Docking and Molecular Dynamics Simulation Studies of Human Pancreatic α-Amylase with Phytochemicals from Corydalis chaerophylla D.C.

Abstract

Diabetes mellitus, a chronic metabolic disorder resulting from hyperglycemia, is responsible for millions of deaths worldwide. The hyperglycemic index can be reduced through the inhibition of human pancreatic α-amylase (HPAA), an enzyme associated with the cleavage of α-(1,4)-D-glycosidic bonds for the conversion of starch into glucose molecules. Six alkaloids of a medicinally important plant, Corydalis chaerophylla, were studied through an in silico method to determine their potential role as HPAA inhibitors and for molecular-level understanding. Two ligands, protopine (PTP) and hunnemanine (HNM), showed higher docking scores, yielding binding affinities of -8.8 kcal/mol and -8.7 kcal/mol, respectively, compared with the native ligand myricetin, having a docking score of -7.9 kcal/mol against HPAA (PDB ID: 4GQR) in the molecular docking calculation. Smooth curves with RMSD less than 4 Å and supporting geometrical parameters (RMSF, SASA, gyradius) from molecular dynamics simulations inferred their structural stability and conservation of the docked pose at the catalytic site over time compared to other ligands. The binding free energy changes were calculated as -16.39±2.57 kcal/mol and -18.30±2.81 kcal/mol for the ligands PTP and HNM, respectively, and indicated the spontaneity of the adduct formation reaction. This study proposed two alkaloids, PTP and HNM, as hit candidates against the target HPAA. The pharmacokinetics and toxicity profiles of these candidates additionally supported their drug-like nature. The results of the study suggested possible diabetes management by the proposed compounds, and recommendations for further in vitro and in vivo biocharacterization are proposed to validate the inferences of this study.