Investigating the potential of 6-substituted 3-formyl chromone derivatives as anti-diabetic agents using in silico methods

Abstract

In exploring nature's potential in addressing diabetes-related conditions, this study investigates the therapeutic capabilities of 3-formyl chromone derivatives. Utilizing in silico methodologies, we focus on 6-substituted 3-formyl chromone derivatives (1-16) to assess their therapeutic potential in treating diabetes. The research examined the formyl group at the chromone's C-3 position. ADMET, biological activities, were conducted along with B3LYP calculations using 3 different basis sets. The analogues were analyzed based on their parent structure obtained from PubChem. The HOMO-LUMO gap confirmed the bioactive nature of the derivatives, NBO analysis was performed to understand the charge transfer. PASS prediction revealed that 3-formyl chromone derivatives are potent aldehyde oxidase inhibitors, insulin inhibitors, HIF1A expression inhibitors, and histidine kinase. Molecular docking studies indicated that the compounds had a strong binding affinity with proteins, including CAD, BHK, IDE, HIF-α, p53, COX, and Mpro of SARS-CoV2. 6-isopropyl-3-formyl chromone (4) displayed the highest affinity for IDE, with a binding energy of - 8.5 kcal mol^-1. This result outperformed the affinity of the reference standard dapagliflozin (- 7.9 kcal mol^-1) as well as two other compounds that target human IDE, namely vitexin (- 8.3 kcal mol^-1) and myricetin (- 8.4 kcal mol^-1). MD simulations were revealed RMSD value between 0.2 and 0.5 nm, indicating the strength of the protein-ligand complex at the active site.

Figure 1

Chemical structures of C₆ substituted 3-formyl chromone analogues (Y = EDG or EWG) (1–16).

Figure 2

(a) HOMO and (b) LUMO with Egap; (c) Maps of electrostatic potential (0.02 electrons bohr⁻³ surface) (red = electron-rich, blue = electron-deficient) for compound 4. Regions of respective colours indicating electrophilic (blue) and nucleophilic (red) sites and partial nucleophilic sites (yellow regions); (d) NBO charges for compound 4.

Figure 3

Molecular docking poses: (a) Ligand in protein pocket; (b) Active site; (c) Hydrogen bonding in solid; (d) Ligand–protein interaction for 2D diagram of compound 4 and modeled protein (IDE).

Figure 4

Molecular docking poses: (a) Ligand in protein pocket; (b) Active site; (c) Hydrogen bonding in solid; (d) Ligand–protein interaction for 2D diagram of compound 4 and modeled protein (COX).

Figure 5

RMSD evolution for merge docked protein–ligand complex between two proteins and modeled ligand 4, (IDE (6BF8), green line and COX (6Y3C), (4, red and black), water and ions in the ligand-IDE protein complex (yellow) and water and ions in the ligand-COX protein complex (brown) during 20 ns MD simulation.

Figure 6

RMSF evolution for the IDE protein–ligand complex (black) and the COX protein–ligand complex (red) and modeled ligand 4, during 20 ns MD simulation.

Figure 7

Radius of gyration, Rg (nm) versus time (ps) plots of the ligand (R_g), IDE protein–ligand complex (Rg_X), COX protein–ligand complex (Rg_Y) and water-ions (Rg_Z,) with modeled ligand 4, during 20 ns MD simulation.

Figure 8

Plots of the number of hydrogen bond versus time (ps) for (a) between protein complex of PDB: 6BF8 and compound 4 and (b) between protein complex of PDB: 6Y3C and compound 4 during 20 ns MD simulation.

Figure 9

The temperature and potential energy curves over the course of the 20 ns MD simulation for the potential energy graph for the protein–ligand complex of IDE (a) and COX (c); the temperature graph of the protein–ligand complex of IDE (b) and COX (d) with compound 4.

Figure 10

PCA of the IDE complex with compound 4 at 300 K MD trajectory, where red dots represent stable conformations and black dots indicate energetically unstable conformations.