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<p>The inhibition of α-amylase is a critical therapeutic target for managing postprandial hyperglycemia in type 2 diabetes. In this study, an integrated computational strategy combining 3D-QSAR modeling, ADMET profiling, molecular docking, and molecular dynamics simulations was deployed to identify novel, potent α-amylase inhibitors derived from a 1,3,4-thiadiazole scaffold. The optimal 3D-QSAR model demonstrated robust correlation and predictive performance, revealing that electrostatic and hydrophobic fields are the primary determinants of the biological activity of these molecules. Leveraging these structural insights, two new derivatives (PR1 and PR2) were designed, exhibiting predicted enhanced inhibitory activities and favorable pharmacokinetic and toxicological profiles. Molecular docking confirmed that both compounds fit precisely within the active site of the 1B2Y protein with acceptable affinities. Furthermore, molecular dynamics simulations results showed that PR1-receptor complex exhibits exceptional structural stability and superior binding profile compared to the most commonly used drug, acarbose. These findings suggest that PR1 and PR2 are promising candidates for advanced antidiabetic drug development.</p>

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Design of novel derivatives of 1,3,4-thiadiazole against the α-amylase enzyme using 3D-QSAR, ADMET evaluation, docking analysis, molecular dynamic simulations and MM-PBSA approaches

  • 期刊论文

  • 发表日期：

    2026年7月27日

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  • Lhoucine Naanaai,
  • Ikram Hanout,
  • Md. Al-Amin,
  • Fouad Khalil,
  • Abdellatif Lamhamdi

摘要

The inhibition of α-amylase is a critical therapeutic target for managing postprandial hyperglycemia in type 2 diabetes. In this study, an integrated computational strategy combining 3D-QSAR modeling, ADMET profiling, molecular docking, and molecular dynamics simulations was deployed to identify novel, potent α-amylase inhibitors derived from a 1,3,4-thiadiazole scaffold. The optimal 3D-QSAR model demonstrated robust correlation and predictive performance, revealing that electrostatic and hydrophobic fields are the primary determinants of the biological activity of these molecules. Leveraging these structural insights, two new derivatives (PR1 and PR2) were designed, exhibiting predicted enhanced inhibitory activities and favorable pharmacokinetic and toxicological profiles. Molecular docking confirmed that both compounds fit precisely within the active site of the 1B2Y protein with acceptable affinities. Furthermore, molecular dynamics simulations results showed that PR1-receptor complex exhibits exceptional structural stability and superior binding profile compared to the most commonly used drug, acarbose. These findings suggest that PR1 and PR2 are promising candidates for advanced antidiabetic drug development.