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<p>Phosphatidylinositol-3 kinase (PI3K) regulates cellular growth, survival, differentiation, and proliferation. PI3KA gene mutations occur in 30–50% of cancers, including breast, colorectal, and ovarian. This study applies a QSAR approach to thieno[2,3-d]pyrimidine derivatives targeting PI3Kα. QSAR Model 2 demonstrated strong predictive capability (R<sup>2</sup> = 0.9616, Q<sup>2</sup> = 0.9362, R<sup>2</sup>ext = 0.9721, SEE = 0.1356). Key descriptors (AATSC6v, SpMin4_Bhm, ZMIC1, RotBFrac) influenced activity, suggesting alkyl chains at position 7 and electron-rich substituents at position 4 enhance therapeutic potential. Based on SAR and QSAR insights, 25 new thienopyrimidine derivatives were designed, with the top 10 screened for docking and ADMET against PI3Kα. BTP20 exhibited the highest predicted activity (2.2161) and superior binding affinity (-7.23&#xa0;kcal/mol) over alpelisib (-6.21&#xa0;kcal/mol), forming key hydrogen bonds between etheryl oxygen with SerB339, thienopyrimidine with ArgA1023 and the amine group on the furan ring with GluA950 along with hydrophobic contacts. DFT analysis confirmed its chemical stability and reactivity. MD simulations validated BTP20-PI3Kα complex stability (average protein RMSD: 3.0 Å, ligand RMSD: 3.6–4.5 Å, protein RMSF: 3 Å and ligand RMSF: 2 Å). These findings position BTP20 as a promising PI3Kα inhibitor with favorable binding, stability, and chemical properties for further development.</p>

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QSAR-based design and computational evaluation of thieno[2,3-d]pyrimidine derivatives as potential PI3Kα inhibitors

  • 期刊论文

  • 发表日期：

    2026年4月18日

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  • Bhuvaneswari Sivaraman,
  • Kathiravan Muthukumaradoss

摘要

Phosphatidylinositol-3 kinase (PI3K) regulates cellular growth, survival, differentiation, and proliferation. PI3KA gene mutations occur in 30–50% of cancers, including breast, colorectal, and ovarian. This study applies a QSAR approach to thieno[2,3-d]pyrimidine derivatives targeting PI3Kα. QSAR Model 2 demonstrated strong predictive capability (R2 = 0.9616, Q2 = 0.9362, R2ext = 0.9721, SEE = 0.1356). Key descriptors (AATSC6v, SpMin4_Bhm, ZMIC1, RotBFrac) influenced activity, suggesting alkyl chains at position 7 and electron-rich substituents at position 4 enhance therapeutic potential. Based on SAR and QSAR insights, 25 new thienopyrimidine derivatives were designed, with the top 10 screened for docking and ADMET against PI3Kα. BTP20 exhibited the highest predicted activity (2.2161) and superior binding affinity (-7.23 kcal/mol) over alpelisib (-6.21 kcal/mol), forming key hydrogen bonds between etheryl oxygen with SerB339, thienopyrimidine with ArgA1023 and the amine group on the furan ring with GluA950 along with hydrophobic contacts. DFT analysis confirmed its chemical stability and reactivity. MD simulations validated BTP20-PI3Kα complex stability (average protein RMSD: 3.0 Å, ligand RMSD: 3.6–4.5 Å, protein RMSF: 3 Å and ligand RMSF: 2 Å). These findings position BTP20 as a promising PI3Kα inhibitor with favorable binding, stability, and chemical properties for further development.