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<p>CaMKIIα is a central regulator of synaptic plasticity and memory, and its pathological overactivation has been strongly linked to neurodegenerative and neuropsychiatric disorders. However, there remains a significant demand for discovery of potent and novel CaMKIIα inhibitors. This study constructed an integrated virtual screening workflow that combined machine learning, molecular docking, and drug-likeness evaluation. By screening 1.55 million compounds from the ChemDiv library, 10 candidates selected for subsequent experimental validation. Among these, an oxadiazole derivative, compound <b>2</b>, was identified as a novel inhibitor with an IC<sub>50</sub> of 3.18&#xa0;µM, introducing a novel scaffold for CaMKIIα inhibition. Molecular dynamics simulations was performed to demonstrated the stability of the CaMKIIα-compound <b>2</b> complex and the contribution of specific residues. This work provides a practical framework for the virtual screening of kinase inhibitors and presents a novel hit for CaMKIIα-targeted drug development.</p> Graphical Abstract <p></p>

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Discovery of a novel CaMKⅡα inhibitor by machine learning, molecular docking and molecular dynamics simulation

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Tianze Shen,
  • Long Chen,
  • Yunlin Liu,
  • Yanze Li,
  • Yang Wang,
  • Xiaoli Li,
  • Weilie Xiao,
  • Ruihan Zhang

摘要

CaMKIIα is a central regulator of synaptic plasticity and memory, and its pathological overactivation has been strongly linked to neurodegenerative and neuropsychiatric disorders. However, there remains a significant demand for discovery of potent and novel CaMKIIα inhibitors. This study constructed an integrated virtual screening workflow that combined machine learning, molecular docking, and drug-likeness evaluation. By screening 1.55 million compounds from the ChemDiv library, 10 candidates selected for subsequent experimental validation. Among these, an oxadiazole derivative, compound 2, was identified as a novel inhibitor with an IC50 of 3.18 µM, introducing a novel scaffold for CaMKIIα inhibition. Molecular dynamics simulations was performed to demonstrated the stability of the CaMKIIα-compound 2 complex and the contribution of specific residues. This work provides a practical framework for the virtual screening of kinase inhibitors and presents a novel hit for CaMKIIα-targeted drug development.

Graphical Abstract