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<p>Human tetraplex (G-quadruplexes) are unique four-stranded DNA structures formed in guanine-rich regions which are recognized as important targets in anticancer drug discovery due to their role in regulating oncogene expression and maintaining genomic stability. Triethylenetetramine (TETA) has shown potential as an anticancer agent by stabilizing G-quadruplexes, inhibiting telomerase, inducing cellular senescence, and exhibiting selectivity toward cancer cells. However, its binding behavior varies depending on the topology and sequence of G-quadruplexes. In this study, we performed molecular docking of TETA with four different G-quadruplexes, followed by a 200-ns molecular dynamics simulation in explicit solvent on the most promising complex. Energetic and structural parameters, including binding free energy, entropy, RMSD, RMSF, number of hydrogen bond, hydrogen bond distance and dihedral angle, were analyzed. Our results demonstrate that the conformational flexibility of TETA manifested through its ability to adopt flip-flop conformations due to symmetry presented around hindered C–C bond rotation plays a crucial role to specific and stable interactions within the G-quadruplex cavity, especially in intermolecular forms, contributing to enhanced stabilization and functional inhibition of telomerase. Moreover, these findings provide mechanistic insights that may aid in designing more efficient derivatives for targeted cancer therapy.</p>

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In Silico Study of Triethylenetetramine Binding to Human Tetraplex DNA: Insights into Anticancer Activity

  • 期刊论文

  • 发表日期：

    2025年9月25日

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  • Km. Vandana,
  • Rakesh Kumar Tiwari,
  • Muralidhar,
  • Apara Tripathi

摘要

Human tetraplex (G-quadruplexes) are unique four-stranded DNA structures formed in guanine-rich regions which are recognized as important targets in anticancer drug discovery due to their role in regulating oncogene expression and maintaining genomic stability. Triethylenetetramine (TETA) has shown potential as an anticancer agent by stabilizing G-quadruplexes, inhibiting telomerase, inducing cellular senescence, and exhibiting selectivity toward cancer cells. However, its binding behavior varies depending on the topology and sequence of G-quadruplexes. In this study, we performed molecular docking of TETA with four different G-quadruplexes, followed by a 200-ns molecular dynamics simulation in explicit solvent on the most promising complex. Energetic and structural parameters, including binding free energy, entropy, RMSD, RMSF, number of hydrogen bond, hydrogen bond distance and dihedral angle, were analyzed. Our results demonstrate that the conformational flexibility of TETA manifested through its ability to adopt flip-flop conformations due to symmetry presented around hindered C–C bond rotation plays a crucial role to specific and stable interactions within the G-quadruplex cavity, especially in intermolecular forms, contributing to enhanced stabilization and functional inhibition of telomerase. Moreover, these findings provide mechanistic insights that may aid in designing more efficient derivatives for targeted cancer therapy.