Antidiabetic Potential of Synthesized Ferrocenylmethylaniline Derivatives: Insights From In Vitro Studies, Molecular Docking, ADMET, DFT Calculations, and Molecular Dynamics Simulation.

Abstract

This study investigates the potential of three synthesized ferrocenylmethylaniline derivatives (FMBA, FMAA, and FMA) as inhibitors of α-amylase, a key enzyme involved in the pathophysiology of diabetes. In vitro inhibition assays demonstrated that FMBA and FMAA exhibited significantly lower IC50 values of 9.23 and 11.23 µM, respectively, compared to 259 µM for the standard drug acarbose (ARE). Molecular docking studies supported these findings, with FMBA showing the highest binding affinity (∆G of -7.33 kcal/mol), followed by FMAA (-6.44 kcal/mol) and FMA (-5.85 kcal/mol), outperforming ARE (-4.88 kcal/mol). ADMET analysis suggested favorable pharmacokinetic and safety profiles for FMBA and FMAA, reinforcing their potential as viable drug candidates. To further assess the stability and dynamics of the enzyme-ligand interactions, molecular dynamics simulations were conducted, showing that FMBA and FMAA formed significantly more stable complexes with α-amylase compared to ARE, as indicated by low root mean square deviation (RMSD) values of 0.156 and 0.164 nm, respectively, compared to 0.359 nm for ARE. Root mean square fluctuation (RMSF) analysis revealed consistent stability at key active site residues. Additional analyses of radius of gyration (R_g) and solvent-accessible surface area (SASA) supported the compact and stable nature of the complexes. Frontier molecular orbital (FMO) analysis showed smaller HOMO-LUMO energy gaps for FMBA and FMAA, suggesting greater reactivity and potential biological activity. Molecular electrostatic potential (MEP) surface analysis highlighted key reactive sites, with high negative potential localized on the carbonyl groups of FMBA and FMAA, and high positive potential in regions favoring hydrogen bonding. These findings underscore the potential of FMBA and FMAA as promising antidiabetic agents and support their further development as therapeutic candidates.