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<p>AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500&#xa0;ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds <b>DVK5 and DVK11</b> were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of <b>−&#xa0;9.863 and –&#xa0;8.994&#xa0;kcal/mol</b>, respectively. Molecular dynamics simulations further revealed that the <b>DVK5 and DVK11</b> complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500&#xa0;ns simulation. Additionally, in silico ADMET analysis demonstrated that <b>DVK10</b> exhibited an excellent human oral absorption rate of <b>75.175%</b>, outperforming other compounds in the series. These findings strongly suggest the potential of <b>DVK5 and DVK11</b> as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.</p>

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In silico investigation of thiazole–semicarbazide hybrids as dual GSK-3β/Tau inhibitors for Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Dileep Kumar,
  • Vinayak Walhekar,
  • K. Mangala Shenoy,
  • Suvarna G. Kini

摘要

AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500 ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds DVK5 and DVK11 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of − 9.863 and – 8.994 kcal/mol, respectively. Molecular dynamics simulations further revealed that the DVK5 and DVK11 complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that DVK10 exhibited an excellent human oral absorption rate of 75.175%, outperforming other compounds in the series. These findings strongly suggest the potential of DVK5 and DVK11 as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.