Exploring the α-Amylase, α-Glucosidase Inhibition of Acyl hydrazone Derivatives: In Vitro, Molecular Docking, Dynamics Simulation, ADMET and DFT Studies
Aftab Alam, Huma Rafiq, Muhammad Ismail, Imtiaz Ahmad, Mohammad Assad, Muhammad Naseer Abbas, Mohammed M. Alanazi, Ashwag S. Alanazi, Masroor Kamal, Ahmed Abdlmonem El-Henawy, Momin Khan · Journal of Computational Biophysics and Chemistry · 2025
This study investigates the potential of acyl hydrazone derivatives (2a-n) of 4-fluorobenzoic acid as dual inhibitors of [Formula: see text]amylase and [Formula: see text]glucosidase enzymes that are critical in carbohydrate metabolism and diabetes management. Through in vitro assays, molecular docking, density functional theory (DFT), ADME analysis and molecular dynamics simulations, we identified several potent compounds with IC[Formula: see text] values ranging from 4.91 ± 1.29 [Formula: see text]M to 14.21 ± 1.09 [Formula: see text]M for both enzymes, surpassing the standard drug acarbose. Notably, compound 2a (2,4-dichlorophenyl) emerged as the most promising dual inhibitor due to its optimal binding interactions with catalytic residues such as (ASP300, TYR62 and HIS305) in [Formula: see text]amylase, and (ASP282 and ASP404) in [Formula: see text]glucosidase. DFT analysis revealed that halogenated substituents, particularly chlorine atoms at ortho and para positions, significantly enhanced electrophilicity and inhibitory potency. Molecular dynamics simulations demonstrated that compounds (2aand 2f) effectively stabilized the enzymes in a closed conformation, restricting substrate access and reducing structural flexibility in the catalytic domains. These findings underscore the importance of electron-withdrawing groups in enhancing enzyme inhibition and highlight the therapeutic potential of halogen-substituted acyl hydrazones as anti-diabetic agents. Future research will focus on optimizing substitution patterns and conducting in vivo studies to validate these results.