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<p>Colorectal cancer (CRC) is one of the most dominant malignancies worldwide, with Cytochrome P450 CYP17A1 playing a significant role in its progression. In this study, quinazoline derivatives were screened for their potential as CYP17A1 inhibitors using molecular docking, virtual screening, solvent-accessible surface area, cytotoxicity analysis and molecular dynamics (MD) simulations. Despite advancements in diagnostic and therapeutic approaches, early detection and targeted treatment strategies are still limited. A total of 69 quinazoline derivatives were initially selected and optimized using the OPLS4 force field, with 45 compounds meeting Lipinski’s Rule of Five. Molecular docking was conducted using the PyRx tool, identifying FR10, FR12, and FR28 as lead candidates, with binding energies surpassing Fruquintinib (-8.8&#xa0;kcal/mol), the standard inhibitor. Among them, FR12 exhibited the strongest binding (-9.9&#xa0;kcal/mol), forming hydrogen bonds with CYS442, ALA105, and ASN202. MD simulations (100&#xa0;ns) and MM-GBSA analysis were performed using GROMACS to assess binding stability of hit compounds. RMSD analysis confirmed the stability of FR12, with deviations below 3&#xa0;Å, while RMSF analysis highlighted minimal fluctuations within the active site. Protein–Protein Interaction (PPI) analysis using STRING mapped interaction networks, identifying key functional clusters relevant to CRC. The Protein Contacts Atlas further validated structural integrity through chord, asteroid, and scatter plots. This comprehensive study demonstrates that FR12 is a promising CYP17A1 inhibitor with strong binding affinity, stability, and selectivity. These findings pave the way for further pharmacokinetic evaluations and experimental validations, offering potential therapeutic advancements for colorectal cancer treatment.</p>

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Targeting quinazoline derivatives for colorectal cancer: toxicity prediction, molecular docking, dynamics simulation, MM-GBSA calculation and structural insights

  • 期刊论文

  • 发表日期：

    2025年12月19日

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  • Komal Prajapati,
  • Ajay Kumar

摘要

Colorectal cancer (CRC) is one of the most dominant malignancies worldwide, with Cytochrome P450 CYP17A1 playing a significant role in its progression. In this study, quinazoline derivatives were screened for their potential as CYP17A1 inhibitors using molecular docking, virtual screening, solvent-accessible surface area, cytotoxicity analysis and molecular dynamics (MD) simulations. Despite advancements in diagnostic and therapeutic approaches, early detection and targeted treatment strategies are still limited. A total of 69 quinazoline derivatives were initially selected and optimized using the OPLS4 force field, with 45 compounds meeting Lipinski’s Rule of Five. Molecular docking was conducted using the PyRx tool, identifying FR10, FR12, and FR28 as lead candidates, with binding energies surpassing Fruquintinib (-8.8 kcal/mol), the standard inhibitor. Among them, FR12 exhibited the strongest binding (-9.9 kcal/mol), forming hydrogen bonds with CYS442, ALA105, and ASN202. MD simulations (100 ns) and MM-GBSA analysis were performed using GROMACS to assess binding stability of hit compounds. RMSD analysis confirmed the stability of FR12, with deviations below 3 Å, while RMSF analysis highlighted minimal fluctuations within the active site. Protein–Protein Interaction (PPI) analysis using STRING mapped interaction networks, identifying key functional clusters relevant to CRC. The Protein Contacts Atlas further validated structural integrity through chord, asteroid, and scatter plots. This comprehensive study demonstrates that FR12 is a promising CYP17A1 inhibitor with strong binding affinity, stability, and selectivity. These findings pave the way for further pharmacokinetic evaluations and experimental validations, offering potential therapeutic advancements for colorectal cancer treatment.