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<p>Breast cancer heterogeneity and resistance motivate the development of polypharmacological agents that engage multiple oncogenic nodes within a single chemotype. We designed and evaluated 64 coumarin–pyrimidine hybrids—organized into hydroxy- and sulfhydryl-pyrimidine series—against PARP-1, EGFR, HER2, and BCL-2 using an integrated in silico workflow. Molecular docking provided primary ranking and top docking affinities reached − 8.7&#xa0;kcal/mol for PARP-1, − 10.6&#xa0;kcal/mol for EGFR, − 10.1&#xa0;kcal/mol for HER2, and − 8.1&#xa0;kcal/mol for BCL-2, exceeding the reference ligands (olaparib − 6.2; erlotinib − 7.3; lapatinib − 6.9; doxorubicin − 7.0&#xa0;kcal/mol). Molecular dynamics (MD) simulations (200&#xa0;ns) were used to assess pose persistence and protein compactness. MM-GBSA rescoring on MD snapshots refined binding energetics; MM-GBSA ΔG_bind values were as favorable as − 51.10&#xa0;kcal/mol (5&#xa0;m–EGFR) and − 50.94&#xa0;kcal/mol (9&#xa0;s–HER2). Time-resolved MM-PBSA profiles monitored the stability of binding free energy along trajectories, and pharmacophore modeling rationalized key interaction features. Hydroxy-pyrimidines generally outperformed sulfhydryl analogues at PARP-1 and in kinase pockets, with para electron-withdrawing and heteroaryl substituents strengthening hinge-directed hydrogen bonding, π-stacking, and lipophilic packing. Four complexes—5&#xa0;h–4R6E (PARP-1), 6f–1M17 (EGFR), 9&#xa0;s–3RCD (HER2), 10d–4IEH (BCL-2)—showed consistent performance across methods, characterized by low MD fluctuations, compact radius-of-gyration ranges, persistent hydrogen bonds, and persistently favorable MM-PBSA energy profiles. Time-averaged MM-PBSA binding free energies were approximately − 140 to − 160&#xa0;kJ/mol across the four systems. In silico ADMET supported their developability with molecule-specific considerations: 5&#xa0;h (potent, but low predicted oral bioavailability), 6f (drug-like, predicted gastrointestinal absorption and potential blood–brain barrier penetration), 9&#xa0;s (balanced profile with predicted BCRP (breast cancer resistance protein) interaction), and 10d (strong binding with hepatotoxicity alerts to de-risk). These findings nominate 5&#xa0;h, 6f, 9&#xa0;s, and 10d as prioritized computational leads for synthesis and experimental validation in relevant breast cancer models.</p>

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Bioisosteric coumarin–pyrimidine hybrids for multi-target breast-cancer inhibition: an integrated in Silico study

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Veda B. Hacholli,
  • M. R. Shubha,
  • Łukasz Szeleszczuk,
  • B. H. Prabhanjan,
  • Abhishek Kumar,
  • Marcin Gackowski

摘要

Breast cancer heterogeneity and resistance motivate the development of polypharmacological agents that engage multiple oncogenic nodes within a single chemotype. We designed and evaluated 64 coumarin–pyrimidine hybrids—organized into hydroxy- and sulfhydryl-pyrimidine series—against PARP-1, EGFR, HER2, and BCL-2 using an integrated in silico workflow. Molecular docking provided primary ranking and top docking affinities reached − 8.7 kcal/mol for PARP-1, − 10.6 kcal/mol for EGFR, − 10.1 kcal/mol for HER2, and − 8.1 kcal/mol for BCL-2, exceeding the reference ligands (olaparib − 6.2; erlotinib − 7.3; lapatinib − 6.9; doxorubicin − 7.0 kcal/mol). Molecular dynamics (MD) simulations (200 ns) were used to assess pose persistence and protein compactness. MM-GBSA rescoring on MD snapshots refined binding energetics; MM-GBSA ΔG_bind values were as favorable as − 51.10 kcal/mol (5 m–EGFR) and − 50.94 kcal/mol (9 s–HER2). Time-resolved MM-PBSA profiles monitored the stability of binding free energy along trajectories, and pharmacophore modeling rationalized key interaction features. Hydroxy-pyrimidines generally outperformed sulfhydryl analogues at PARP-1 and in kinase pockets, with para electron-withdrawing and heteroaryl substituents strengthening hinge-directed hydrogen bonding, π-stacking, and lipophilic packing. Four complexes—5 h–4R6E (PARP-1), 6f–1M17 (EGFR), 9 s–3RCD (HER2), 10d–4IEH (BCL-2)—showed consistent performance across methods, characterized by low MD fluctuations, compact radius-of-gyration ranges, persistent hydrogen bonds, and persistently favorable MM-PBSA energy profiles. Time-averaged MM-PBSA binding free energies were approximately − 140 to − 160 kJ/mol across the four systems. In silico ADMET supported their developability with molecule-specific considerations: 5 h (potent, but low predicted oral bioavailability), 6f (drug-like, predicted gastrointestinal absorption and potential blood–brain barrier penetration), 9 s (balanced profile with predicted BCRP (breast cancer resistance protein) interaction), and 10d (strong binding with hepatotoxicity alerts to de-risk). These findings nominate 5 h, 6f, 9 s, and 10d as prioritized computational leads for synthesis and experimental validation in relevant breast cancer models.