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Background <p>Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide. Although curcumin has shown promising anticancer activity, its therapeutic application is limited by poor bioavailability, rapid metabolism, and low stability, necessitating the identification of derivatives with improved pharmacological properties. </p> Methods <p>In this study, we employed an integrated network pharmacology and computational modeling framework to identify curcumin derivatives targeting CRC. </p> Results <p>SuperPred3 and CLC-Pred 2.0 identified 106 and 221 potential curcumin targets, respectively, while DisGeNET retrieved 5,474 CRC-associated genes. Overlapping these datasets yielded 68 common targets, with protein–protein interaction (PPI) network analysis and CytoHubba ranking identifying STAT3 as the top-ranked hub gene. Molecular docking-based screening of compounds from the Curcumin Chalcone Compound Database (CCCD) prioritized two lead derivatives, PubChem CID 122,378,841 and 135,494,223, which exhibited stronger binding affinities (− 8.294 and − 8.133 kcal/mol, respectively) than curcumin (− 7.169 kcal/mol). These compounds formed stable interactions with key STAT3 residues, including Ser613, Ser611, and Lys591. Extensive 200 ns molecular dynamics simulations, supported by principal component analysis (PCA) and free energy landscape (FEL) analyses, confirmed the structural stability of these complexes within the SH2-domain binding pocket of STAT3. MM/GBSA analysis further corroborated these findings, with 122,378,841–STAT3 and 135,494,223–STAT3 showing more favorable total binding free energies (− 45.91 ± 0.45 and − 44.76 ± 0.52 kcal/mol, respectively) than curcumin–STAT3 (− 38.31 ± 0.31 kcal/mol). In addition, density functional theory (DFT) analysis suggested that the selected derivatives possess greater kinetic stability and electrophilic character than curcumin, consistent with stronger interactions with STAT3. ADMET and physicochemical profiling further indicated favorable drug-likeness, predicted absorption, and pharmacokinetic properties of the derivatives.</p> Conclusion <p>Collectively, these findings identify 122,378,841 and 135,494,223 as computationally prioritized STAT3-targeting curcumin derivatives in CRC and provide a mechanistically informed basis for further in vitro and in vivo validation of their biological activity, safety, and therapeutic relevance.</p>

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Integrative Network Pharmacology and Molecular Dynamics Simulation Uncover Key Molecular Targets of Curcumin and Its Derivatives in Colorectal Cancer

  • 期刊论文

  • 发表日期：

    2026年5月4日

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  • Usama Ilahi,
  • Muhammad Suleman,
  • Abrar Mohammad Sayaf,
  • Muhammad Rizwan,
  • Fazal Akbar,
  • Zafar Ali,
  • Haji Khan,
  • Zahid Hussain,
  • Mohammad Ali,
  • Hadi M. Yassine,
  • Abdullah A. Shaito,
  • Sergio Crovella

摘要

Background

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide. Although curcumin has shown promising anticancer activity, its therapeutic application is limited by poor bioavailability, rapid metabolism, and low stability, necessitating the identification of derivatives with improved pharmacological properties.

Methods

In this study, we employed an integrated network pharmacology and computational modeling framework to identify curcumin derivatives targeting CRC.

Results

SuperPred3 and CLC-Pred 2.0 identified 106 and 221 potential curcumin targets, respectively, while DisGeNET retrieved 5,474 CRC-associated genes. Overlapping these datasets yielded 68 common targets, with protein–protein interaction (PPI) network analysis and CytoHubba ranking identifying STAT3 as the top-ranked hub gene. Molecular docking-based screening of compounds from the Curcumin Chalcone Compound Database (CCCD) prioritized two lead derivatives, PubChem CID 122,378,841 and 135,494,223, which exhibited stronger binding affinities (− 8.294 and − 8.133 kcal/mol, respectively) than curcumin (− 7.169 kcal/mol). These compounds formed stable interactions with key STAT3 residues, including Ser613, Ser611, and Lys591. Extensive 200 ns molecular dynamics simulations, supported by principal component analysis (PCA) and free energy landscape (FEL) analyses, confirmed the structural stability of these complexes within the SH2-domain binding pocket of STAT3. MM/GBSA analysis further corroborated these findings, with 122,378,841–STAT3 and 135,494,223–STAT3 showing more favorable total binding free energies (− 45.91 ± 0.45 and − 44.76 ± 0.52 kcal/mol, respectively) than curcumin–STAT3 (− 38.31 ± 0.31 kcal/mol). In addition, density functional theory (DFT) analysis suggested that the selected derivatives possess greater kinetic stability and electrophilic character than curcumin, consistent with stronger interactions with STAT3. ADMET and physicochemical profiling further indicated favorable drug-likeness, predicted absorption, and pharmacokinetic properties of the derivatives.

Conclusion

Collectively, these findings identify 122,378,841 and 135,494,223 as computationally prioritized STAT3-targeting curcumin derivatives in CRC and provide a mechanistically informed basis for further in vitro and in vivo validation of their biological activity, safety, and therapeutic relevance.