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<p>The aggressive progression of head and neck cancer (HNC) and the limited availability of effective targeted therapies render it as a significant global health challenge. Several key biological pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, AMPK, and glycolysis, play crucial roles in the progression of HNC. Although conventional therapies such as chemotherapy remain widely utilized, there is a pressing need for innovative interventions to address the major limitations of these approaches. In response to this critical issue, this study seeks to evaluate the efficacy of the FDA-approved drug metformin as an anti-cancer agent. To identify and assess the inhibition of these biological molecules by metformin analogs, we employed a comprehensive in-silico approach that integrated molecular docking, molecular dynamics (MD) simulations, and MM/PBSA (Molecular Mechanics/Poisson–Boltzmann Surface Area) free energy calculations. PubChem compound CID 222300 emerged as a top-scoring ligand with a high binding affinity for the mTOR protein (PDB: 4JSV). A 100&#xa0;ns MD simulation was conducted to evaluate the stability and conformational dynamics of the mTOR–ligand complex. The results demonstrated favourable interaction characteristics, including a consistently decreasing radius of gyration (Rg), low root mean square fluctuation (RMSF), and stable root mean square deviation (RMSD), indicating overall structural compaction and stability. Further evidence from hydrogen bond analysis revealed that the ligand contributed to complex stability by maintaining sporadic yet regular polar interactions throughout the trajectory. These findings suggest that CID 222300 is a promising lead compound capable of interacting with the mTOR target in a stable and targeted manner, indicating its potential as a novel therapeutic agent against HNC.</p>

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Investigation of metformin analogues in targeting signaling molecules of head and neck cancer pathways by computational approaches

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Payas Arora,
  • Shiva Prasad Kollur,
  • Pallavi M. Shanthappa,
  • Bhawana Yadav,
  • Manish Tenguria,
  • Nishant Rai,
  • Vijay Jagdish Upadhye,
  • Pallavi Singh

摘要

The aggressive progression of head and neck cancer (HNC) and the limited availability of effective targeted therapies render it as a significant global health challenge. Several key biological pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, AMPK, and glycolysis, play crucial roles in the progression of HNC. Although conventional therapies such as chemotherapy remain widely utilized, there is a pressing need for innovative interventions to address the major limitations of these approaches. In response to this critical issue, this study seeks to evaluate the efficacy of the FDA-approved drug metformin as an anti-cancer agent. To identify and assess the inhibition of these biological molecules by metformin analogs, we employed a comprehensive in-silico approach that integrated molecular docking, molecular dynamics (MD) simulations, and MM/PBSA (Molecular Mechanics/Poisson–Boltzmann Surface Area) free energy calculations. PubChem compound CID 222300 emerged as a top-scoring ligand with a high binding affinity for the mTOR protein (PDB: 4JSV). A 100 ns MD simulation was conducted to evaluate the stability and conformational dynamics of the mTOR–ligand complex. The results demonstrated favourable interaction characteristics, including a consistently decreasing radius of gyration (Rg), low root mean square fluctuation (RMSF), and stable root mean square deviation (RMSD), indicating overall structural compaction and stability. Further evidence from hydrogen bond analysis revealed that the ligand contributed to complex stability by maintaining sporadic yet regular polar interactions throughout the trajectory. These findings suggest that CID 222300 is a promising lead compound capable of interacting with the mTOR target in a stable and targeted manner, indicating its potential as a novel therapeutic agent against HNC.