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<p>Phosphatidylinositol 3-kinase α (PI3Kα) plays a key role in intracellular signaling. PI3Kα catalyzes the conversion of phosphatidylinositol-4,5-diphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), which activates of the PI3K/Akt pathway that is will driving the generation of tumors. PI3Kα inhibitors block PI3Kα activity, and suppress downstream AKT/mTOR pathway, which reduce the growth, survival, migration and invasion of tumor cell. In this study, novel PI3Kα inhibitors were designed based on our constructed three-dimensional quantitative structure–activity relationship models using the 41 2-methyl-1H-imidazo[4,5-c] quinoline derivatives from references. The potential bioactivities estimate of the novel inhibitors were performed by using DFT, ADME/T, Docking, and molecular dynamics simulations. five novel compounds, with higher inhibitory activities than the template compound 36, were designed based on the two reliability and robustness 3D-QSAR models, comparative molecular field analysis (CoMFA) model (q<sup>2</sup> = 0.675, <i>n</i> = 4, r<sup>2</sup> = 0.939), and comparative molecular similarity index analysis (CoMSIA) model (q<sup>2</sup> = 0.589, <i>n</i> = 3, r<sup>2</sup> = 0.937). DFT showed the novel inhibitors have rational low energy gap, and molecular surface electrostatic potential. Results of the ADMET and synthesis evaluation showed that the novel compounds had good ADME/T properties and synthesis potential. Molecular docking revealed the key residues of protein such as VAL851, SER854 and ILE932 play import roles in protein–ligand interactions. The DCCM and PCA analysis of Molecular dynamics simulations have also shown that the key residues of target protein are strongly bound to the novel inhibitors, and higher activity compound L3 showed promising inhibitory activity, suggesting it has potential to be effective PI3Kα inhibitor.</p>

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Design of Novel PI3Kα Inhibitors by Combining 3D-QSAR, ADMET Screening, Molecular Docking, and Molecular Dynamics Simulations

  • 期刊论文

  • 发表日期：

    2025年9月24日

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  • Maoqi Wang,
  • Xingyu Liu,
  • Xiaodie Chen,
  • Jiali Li,
  • Rong Liu,
  • Liang Zou,
  • Weichen Yang,
  • Yueyue He,
  • Mao Shu

摘要

Phosphatidylinositol 3-kinase α (PI3Kα) plays a key role in intracellular signaling. PI3Kα catalyzes the conversion of phosphatidylinositol-4,5-diphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), which activates of the PI3K/Akt pathway that is will driving the generation of tumors. PI3Kα inhibitors block PI3Kα activity, and suppress downstream AKT/mTOR pathway, which reduce the growth, survival, migration and invasion of tumor cell. In this study, novel PI3Kα inhibitors were designed based on our constructed three-dimensional quantitative structure–activity relationship models using the 41 2-methyl-1H-imidazo[4,5-c] quinoline derivatives from references. The potential bioactivities estimate of the novel inhibitors were performed by using DFT, ADME/T, Docking, and molecular dynamics simulations. five novel compounds, with higher inhibitory activities than the template compound 36, were designed based on the two reliability and robustness 3D-QSAR models, comparative molecular field analysis (CoMFA) model (q2 = 0.675, n = 4, r2 = 0.939), and comparative molecular similarity index analysis (CoMSIA) model (q2 = 0.589, n = 3, r2 = 0.937). DFT showed the novel inhibitors have rational low energy gap, and molecular surface electrostatic potential. Results of the ADMET and synthesis evaluation showed that the novel compounds had good ADME/T properties and synthesis potential. Molecular docking revealed the key residues of protein such as VAL851, SER854 and ILE932 play import roles in protein–ligand interactions. The DCCM and PCA analysis of Molecular dynamics simulations have also shown that the key residues of target protein are strongly bound to the novel inhibitors, and higher activity compound L3 showed promising inhibitory activity, suggesting it has potential to be effective PI3Kα inhibitor.