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<p>Cyclin-dependent kinase 2 (CDK2) is an essential regulator of cell cycle progression and a potential target for cancer treatment. Although Andrographolides, the bioactive diterpenoid lactones obtained from Andrographis paniculata, have shown a variety of pharmacological effects, their mechanistic potential as CDK2 inhibitors is rarely explored. This work utilised a thorough in silico methodology to assess specific andrographolides as inhibitors of CDK2. Structural and electronic investigations, encompassing HOMO-LUMO calculations, NBO analysis, and RDG studies, demonstrated advantageous electronic characteristics and possible reactive sites that facilitate robust interactions with CDK2. ADMET calculations indicated satisfactory pharmacokinetic profiles and drug-likeness of the chosen compounds. Molecular docking investigations revealed strong binding affinities, subsequently confirmed by molecular dynamics (MD) simulations that exhibited stable protein-ligand conformations. Calculations of binding free energy utilising MM-GBSA validated robust and persistent interactions, with specific derivatives demonstrating notably advantageous energetics. Our comprehensive computational analysis identifies andrographolides as possible CDK2 inhibitors, offering significant insights for forthcoming experimental validation and prospective development as anticancer agents.</p> Graphical Abstract <p></p>

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Structural, Electronic, and Molecular Dynamics Perspectives of Andrographolides as Potential CDK2 Inhibitors

  • 期刊论文

  • 发表日期：

    2025年11月17日

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  • Jisna Jose,
  • Glowi Alasiri,
  • Jibin K. Varughese,
  • Ali M. Alaseem,
  • Mohammad Fareed,
  • Mohammad Suhail Akhter,
  • Thomas V. Mathew

摘要

Cyclin-dependent kinase 2 (CDK2) is an essential regulator of cell cycle progression and a potential target for cancer treatment. Although Andrographolides, the bioactive diterpenoid lactones obtained from Andrographis paniculata, have shown a variety of pharmacological effects, their mechanistic potential as CDK2 inhibitors is rarely explored. This work utilised a thorough in silico methodology to assess specific andrographolides as inhibitors of CDK2. Structural and electronic investigations, encompassing HOMO-LUMO calculations, NBO analysis, and RDG studies, demonstrated advantageous electronic characteristics and possible reactive sites that facilitate robust interactions with CDK2. ADMET calculations indicated satisfactory pharmacokinetic profiles and drug-likeness of the chosen compounds. Molecular docking investigations revealed strong binding affinities, subsequently confirmed by molecular dynamics (MD) simulations that exhibited stable protein-ligand conformations. Calculations of binding free energy utilising MM-GBSA validated robust and persistent interactions, with specific derivatives demonstrating notably advantageous energetics. Our comprehensive computational analysis identifies andrographolides as possible CDK2 inhibitors, offering significant insights for forthcoming experimental validation and prospective development as anticancer agents.

Graphical Abstract