Investigating the Potential of 6-Substituted 3-Formyl Chromone Derivatives as Anti-Diabetic Agents Using DFT, Molecular Docking and Molecular Dynamics Methods

Abstract

Abstract The focus of this research is to investigate the potential of 6-substituted 3-formyl chromone derivatives (1-16) for various biological activities such as antifungal, antiviral, antibacterial, antiallergenic etc. 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.