New Alpha-Amylase Inhibitory Metabolites from Pericarps of Garcinia mangostana

Abstract

Two new benzophenones: garcimangophenones A (6) and B (7) and five formerly reported metabolites were purified from the pericarps EtOAc fraction of Garcinia mangostana ((GM) Clusiaceae). Their structures were characterized by various spectral techniques and by comparing with the literature. The α-amylase inhibitory (AAI) potential of the isolated metabolites was assessed. Compounds 7 and 6 had significant AAI activity (IC₅₀ 9.3 and 12.2 µM, respectively) compared with acarbose (IC₅₀ 6.4 µM, reference α-amylase inhibitor). On the other hand, 5 had a moderate activity. Additionally, their activity towards the α-amylase was assessed utilizing docking studies and molecular dynamics (MD) simulations. The docking and predictive binding energy estimations were accomplished using reported crystal structure of the α-amylase (PDB ID: 5TD4). Compounds 7 and 6 possessed highly negative docking scores of -11.3 and -8.2 kcal/mol, when complexed with 5TD4, respectively while acarbose had a docking score of -16.1 kcal/mol, when complexed with 5TD4. By using molecular dynamics simulations, the compounds stability in the complexes with the α-amylase was analyzed, and it was found to be stable over the course of 50 ns. The results suggested that the benzophenone derivative 7 may be potential α-amylase inhibitors. However, further investigations to support these findings are required.

Keywords: Clusiaceae; Garcinia mangostana; amylase inhibitory; benzophenones; diabetes; docking study; molecular dynamics.

Figure 1

Structures of the isolated compounds (1–7).

Figure 2

Some key HMBC correlations of compounds 6 and 7.

Figure 3

The α-amylase prepared via Protein Preparation Wizard, Maestro. H-bonding network optimized, and geometry minimized structures of α-amylase PDB ID: 5TD4 complexed with (a) native inhibitor T163, (b) acarbose, (c) compound 7, (d) compound 6, and (e) compound 5.

Figure 4

(a) The inter-molecular contact analysis of protein-ligand complexes and putative binding mode of native inhibitor T163 in the binding site of α-amylase PDB: 5TD4. Native inhibitor is represented as green sticks. The binding site amino acids residues are represented as grey sticks, and H-bonds are represented in yellow dashed lines, (b) 2D depiction of the ligand-protein interactions.

Figure 5

(a) The inter-molecular contact analysis of protein-ligand complexes and putative binding mode of acarbose in the binding site of α = amylase PDB: 5TD4. Acarbose is represented as green sticks. The binding site amino acids residues are represented as grey sticks, and H-bonds are represented in yellow dashed lines, (b) 2D depiction of the ligand-protein interactions.

Figure 6

(a) The inter-molecular contact analysis of protein-ligand complexes and putative binding mode of compound 7 in the binding site of α-amylase PDB: 5TD4. Compound 7 is shown as green sticks. The binding site amino acids residues are represented as grey sticks, and H-bonds are represented in yellow dashed lines, (b) 2D depiction of the ligand-protein interactions.

Figure 7

(a) The inter-molecular contact analysis of protein-ligand complexes and putative binding mode of compound 6 in the binding site of α-amylase PDB: 5TD4. Compound 6 is shown as green sticks. The binding site amino acids residues are represented as grey sticks, and H-bonds are represented in yellow dashed lines, (b) 2D depiction of the ligand-protein interactions.

Figure 8

(a) The inter-molecular contact analysis of protein-ligand complexes and putative binding mode of compound 5 in the binding site of α-amylase PDB: 5TD4. Compound 5 is presented as green sticks. The binding site amino acids residues are represented as grey sticks, and H-bonds are represented in yellow dashed lines, (b) 2D depiction of the ligand-protein interactions.

Figure 9

RMSD analysis for (a) compound 7 and (b) acarbose complexed with α-amylase (PDB Code: 5TD4) of MD simulation trajectory. The 50 ns simulation time asserts the stability of the complex without any changes in the structure.

Figure 10

The α-amylase binding interactions with compound 7 throughout the simulation. The major interactions that occurred are Hydrogen bonds, water bridges, and hydrophobic interaction.

Figure 11

The α-amylase binding interactions with acarbose throughout the simulation. The major interactions that occurred are Hydrogen bonds, water bridges, and hydrophobic interaction.