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<p>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 <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HREI-MS analyses. In vitro enzyme inhibition assays revealed compound 1, bearing a para-CF<sub>3</sub> substituent, as the most potent analogue with IC<sub>50</sub> 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.</p>

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Computationally driven discovery of thieno-pyridine thiadiazoles: a synthesis, DFT, docking and dynamics roadmap toward multitarget antidiabetic therapy

  • 期刊论文

  • 发表日期：

    2026年5月30日

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  • Shoaib Khan,
  • Mohamed A. Habib,
  • Tayyiaba Iqbal,
  • Eman Alzahrani,
  • Aisha Bibi,
  • Nasir Ud Din,
  • Ahmed B. M. Ibrahim,
  • Khasan Kayumov

摘要

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.