Identification of potential human pancreatic α-amylase inhibitors from natural products by molecular docking, MM/GBSA calculations, MD simulations, and ADMET analysis

Abstract

Human pancreatic α-amylase (HPA), which works as a catalyst for carbohydrate hydrolysis, is one of the viable targets to control type 2 diabetes. The inhibition of α-amylase lowers blood glucose levels and helps to alleviate hyperglycemia complications. Herein, we systematically screened the potential HPA inhibitors from a library of natural products by molecular modeling. The modeling encompasses molecular docking, MM/GBSA binding energy calculations, MD simulations, and ADMET analysis. This research identified newboulaside B, newboulaside A, quercetin-3-O-β-glucoside, and sasastilboside A as the top four potential HPA inhibitors from the library of natural products, whose Glide docking scores and MM/GBSA binding energies range from -9.191 to -11.366 kcal/mol and -19.38 to -77.95 kcal/mol, respectively. Based on the simulation, among them, newboulaside B was found as the best HPA inhibitor. Throughout the simulation, with the deviation of 3Å (acarbose = 3Å), it interacted with ASP356, ASP300, ASP197, THR163, ARG161, ASP147, ALA106, and GLN63 via hydrogen bonding. Additionally, the comprehensive ADMET analysis revealed that it has good pharmacokinetic properties having not acutely toxic, moderately bioavailable, and non-inhibitor nature toward cytochrome P450. All the results suggest that newboulaside B might be a promising candidate for drug discovery against type 2 diabetes.

Fig 1

Docked poses and molecular interactions of newboulaside B in the binding site of HPA: (a) 3D molecular surface diagrams, and (b) 2D ligand interactions of newboulaside B with HPA. Glide XP molecular docking contributing term in the HPA and newboulaside B complex: (c) HBOND (hydrogen bond) between HPA and newboulaside B (pink interaction) and (d) PhobEn (hydrophobic enclosure reward) of HPA (CPK gray), and PhobEn of newboulaside B (green ball and stick). The hydrophobic/hydrophilic map is represented as gray/brown patches.

Fig 2

Docked poses and molecular interactions of HPA with inhibitors: 3D molecular surface diagrams and 2D ligand interactions of newboulaside A (a) and (b), quercetin-3-O-β-glucoside (c) and (d), and sasastilboside A (e) and (f), respectively. The hydrogen bonds are represented as pink lines.

Fig 3

RMSD and RMSF analysis of MD simulation trajectory: The RMSD plot obtained for HPA (a) acarbose and newboulaside B complex, and (b) newboulaside A, quercetin-3-O-β-glucoside, and sasastilboside A complex. The RMSF plot was obtained for HPA (c) acarbose complex, and (d) newboulaside B complex. The strand, helix, and loop region of HPA are represented as blue, red, and white, respectively.

Fig 4

Analysis of inhibitor’s molecular interaction and type of contact with HPA after MD simulations: Normalized stacked bar chart of HPA binding site residues interacting with (a) acarbose and (c) newboulaside B via hydrogen bonds, hydrophobic and ionic interactions, and water bridges. Detailed schematic interaction of (b) acarbose and (d) newboulaside B atoms with the binding site residues of HPA. Interactions happening more than 30% of the simulation times are shown.