The present study aims to examine the structural requirements governing α-amylase inhibitory activity of 5-(3-arylallylidene)-2-(arylimino)thiazolidin-4-one derivatives and their precursors by employing a multifaceted approach combining in vitro and in silico studies. The in vitro assay findings revealed strong inhibitory effect of this class of compounds against α-amylase and compound 20 exhibited maximum percentage inhibition of 88.54 ± 0.69, 84.98 ± 0.40, 77.26 ± 0.75, 67.80 ± 0.54, and 62.93 ± 1.17 at 200, 100, 50, 25, and 12.5 µg mL-1, respectively. Multiple CORAL QSAR models were developed from the randomly distributed eight splits by employing two target functions (TF1, TF2 with WCII = 0.0 and = 0.3, respectively), and the quality of predictions by the produced models was validated with the help of various statistical parameters. The model M-4 (R2Val = 0.8799) and model M-11 (R2Val = 0.9064) were the leading models developed by using TF1 and TF2. We designed five new congeneric inhibitors (D-1 to D-5) by incorporating SMILES features positively correlating with the activity. Molecular docking experiments were carried out to confirm the binding of these new inhibitors with the biological receptor α-amylase (PDB ID: 7TAA). Furthermore, molecular dynamic simulations provided a thorough knowledge of the binding process by shedding insight into the dynamic behavior and stability of the ligand-receptor complex over time. The results of this study highlight the key structural characteristics needed for improved α-amylase inhibitory efficacy and provide a rational basis for the development of more effective inhibitors.Communicated by Ramaswamy H. Sarma.
Keywords: ADMET; CORAL; QSAR; Thiazolidin-4-one; molecular docking and dynamics; α-Amylase.