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<p>Colorectal cancer (CRC) remains a major global health challenge, with chronic inflammation and disruption of epithelial polarity identified as key drivers of tumor progression. Polarity complexes such as Scribble–Mutated in Colorectal Cancer (MCC) are central to maintaining epithelial homeostasis, and their dysregulation has been linked to oncogenic transformation. Drug repurposing offers a promising strategy to accelerate therapeutic discovery by identifying new applications for clinically approved agents. In this study, we investigated abrocitinib (ABR), a selective JAK1 inhibitor, as a candidate for repurposing in CRC. Density functional theory (DFT) calculations at the PBE0-D3/6-31G(d) level were used to examine its electronic properties, including geometry optimization, natural bond orbital (NBO) analysis, molecular electrostatic potential (MESP) mapping, and Fukui function analysis. ABR exhibited a moderate HOMO–LUMO gap (1.827&#xa0;eV) and an electrophilicity index of 3.492&#xa0;eV, consistent with favorable reactivity and stability. Molecular docking with the Scribble PDZ1 domain (PDB ID: 6MTV) predicted a strong binding affinity (MolDock score − 78.66&#xa0;kcal/mol; rerank score − 55.69&#xa0;kcal/mol), supported by electrostatic and hydrophobic interactions. Importantly, comparative docking with fluorouracil and capecitabine demonstrated that ABR achieved more favorable binding energies and greater interaction stability than these reference CRC drugs, highlighting its superior potential to disrupt Scribble–MCC interactions. Monte Carlo simulations and normal mode analysis further confirmed the dynamic stability of the ABR–PDZ1 complex. Collectively, these findings provide preliminary evidence that abrocitinib may act as a promising modulator of polarity-regulating protein–protein interactions in CRC. While experimental validation remains necessary, this study establishes a computational framework that supports further biochemical and cellular investigations into abrocitinib’s potential as a repurposed therapeutic candidate.</p>

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Quantum and molecular modelling of abrocitinib as a potential disruptor of cell polarity in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月12日

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  • Gideon E. Mathias,
  • Loveth C. Iwuala,
  • Onyinye J. Ikenyirimba,
  • Stephenie N. Obannaya,
  • Michael R. Ekep-Obasi,
  • Eno E. Ebenso

摘要

Colorectal cancer (CRC) remains a major global health challenge, with chronic inflammation and disruption of epithelial polarity identified as key drivers of tumor progression. Polarity complexes such as Scribble–Mutated in Colorectal Cancer (MCC) are central to maintaining epithelial homeostasis, and their dysregulation has been linked to oncogenic transformation. Drug repurposing offers a promising strategy to accelerate therapeutic discovery by identifying new applications for clinically approved agents. In this study, we investigated abrocitinib (ABR), a selective JAK1 inhibitor, as a candidate for repurposing in CRC. Density functional theory (DFT) calculations at the PBE0-D3/6-31G(d) level were used to examine its electronic properties, including geometry optimization, natural bond orbital (NBO) analysis, molecular electrostatic potential (MESP) mapping, and Fukui function analysis. ABR exhibited a moderate HOMO–LUMO gap (1.827 eV) and an electrophilicity index of 3.492 eV, consistent with favorable reactivity and stability. Molecular docking with the Scribble PDZ1 domain (PDB ID: 6MTV) predicted a strong binding affinity (MolDock score − 78.66 kcal/mol; rerank score − 55.69 kcal/mol), supported by electrostatic and hydrophobic interactions. Importantly, comparative docking with fluorouracil and capecitabine demonstrated that ABR achieved more favorable binding energies and greater interaction stability than these reference CRC drugs, highlighting its superior potential to disrupt Scribble–MCC interactions. Monte Carlo simulations and normal mode analysis further confirmed the dynamic stability of the ABR–PDZ1 complex. Collectively, these findings provide preliminary evidence that abrocitinib may act as a promising modulator of polarity-regulating protein–protein interactions in CRC. While experimental validation remains necessary, this study establishes a computational framework that supports further biochemical and cellular investigations into abrocitinib’s potential as a repurposed therapeutic candidate.