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<p>Hypoxia is a hallmark of the tumor microenvironment, leading to metabolic reprogramming and therapeutic resistance. The enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) supports hypoxia adaptation, making it an attractive target for cancer treatment. Copper-64 diacetyl-bis(N4-methylthiosemicarbazone) (<sup>64</sup>Cu-ATSM) exhibits selective hypoxia uptake, positioning it as a promising theranostic agent for imaging and treating hypoxic tumors. In this study, we employed molecular docking and molecular dynamics (MD) simulations to evaluate the binding, stability, and dynamic behavior of <sup>64</sup>Cu-ATSM within the MTHFD2 active site. Docking analysis revealed strong binding affinity (Δ<i>G</i><sub>bind</sub> = −7.91 kcal/mol) with stable hydrogen bonding to key residues. MD simulations, assessed via root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), radial distribution function (RDF), solvent-accessible surface area (SASA), dynamic cross-correlation maps (DCCM), and 2D principal component analysis (2D-PCA), confirmed ligand stability. MM-PBSA and per-residue decomposition analyses identified ARG43, TYR84, ASN87, LYS88, GLN132, GLY310, GLY313, and PRO314 as key contributors to ligand stabilization. These findings support <sup>64</sup>Cu-ATSM as a potential MTHFD2-targeting theranostic agent. However, in vitro and in vivo studies are needed to validate its therapeutic efficacy, pharmacokinetics, and clinical relevance for hypoxia-selective cancer therapy.</p> Graphical Abstract <p></p>

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Theranostic Potential of Copper-64 ATSM Targeting MTHFD2: An In Silico Perspective on Hypoxia-Selective Imaging and Therapy

  • 期刊论文

  • 发表日期：

    2025年3月24日

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  • Abdulsalam Abuelsamen,
  • Maram B. Alhawarri,
  • Mohammad G. Al-Thiabat,
  • Ghaseb N. Makhadmeh,
  • Tariq AlZoubi,
  • Bilal Harieth Alrimawi,
  • Mohammad A. Khaleel

摘要

Hypoxia is a hallmark of the tumor microenvironment, leading to metabolic reprogramming and therapeutic resistance. The enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) supports hypoxia adaptation, making it an attractive target for cancer treatment. Copper-64 diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) exhibits selective hypoxia uptake, positioning it as a promising theranostic agent for imaging and treating hypoxic tumors. In this study, we employed molecular docking and molecular dynamics (MD) simulations to evaluate the binding, stability, and dynamic behavior of 64Cu-ATSM within the MTHFD2 active site. Docking analysis revealed strong binding affinity (ΔGbind = −7.91 kcal/mol) with stable hydrogen bonding to key residues. MD simulations, assessed via root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), radial distribution function (RDF), solvent-accessible surface area (SASA), dynamic cross-correlation maps (DCCM), and 2D principal component analysis (2D-PCA), confirmed ligand stability. MM-PBSA and per-residue decomposition analyses identified ARG43, TYR84, ASN87, LYS88, GLN132, GLY310, GLY313, and PRO314 as key contributors to ligand stabilization. These findings support 64Cu-ATSM as a potential MTHFD2-targeting theranostic agent. However, in vitro and in vivo studies are needed to validate its therapeutic efficacy, pharmacokinetics, and clinical relevance for hypoxia-selective cancer therapy.

Graphical Abstract