Computationally driven discovery of thieno-pyridine thiadiazoles: a synthesis, DFT, docking and dynamics roadmap...

Diabetes mellitus remains a major metabolic disorder requiring new enzyme-targeted therapies. A series of thieno-pyridine-thiadiazole derivatives (1-10) was synthesized and structurally confirmed by ¹H NMR, ¹³C NMR, and HREI-MS analyses. In vitro enzyme inhibition assays revealed compound 1, bearing a para-CF₃ substituent, as the most potent analogue with IC₅₀ values of 8.30 ± 0.30-8.70 ± 0.20 µM, identifying it as a promising lead scaffold. Computational studies supported these findings. Molecular docking demonstrated favorable binding within enzyme catalytic pockets, while ADMET predictions indicated acceptable drug-likeness and safety parameters. Molecular dynamics simulations confirmed the stability of ligand-enzyme complexes, and pharmacophore modeling highlighted key interaction features responsible for activity. Overall, these combined experimental and computational results suggest that thieno-pyridine-thiadiazole derivatives represent promising candidates for further development as enzyme-targeted antidiabetic agents.