PDF(Pubmed)
Abstract：
In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by evaluating the potential of radioiodinated anastrozole ([125I]anastrozole) and radioiodinated epirubicin ([125I]epirubicin) as targeting agents against MTHFD2-driven tumors. MTHFD2, which is pivotal in one-carbon metabolism, is notably upregulated in various cancers, presenting a novel target for radiopharmaceutical application. Through molecular docking and 200 ns molecular dynamics (MD) simulations, we assess the binding efficiency and stability of [125I]anastrozole and [125I]epirubicin with MTHFD2. Molecular docking illustrates that [125I]epirubicin has a superior binding free energy (∆Gbind) of -41.25 kJ/mol compared to -39.07 kJ/mol for [125I]anastrozole and -38.53 kJ/mol for the control ligand, suggesting that it has a higher affinity for MTHFD2. MD simulations reinforce this, showing stable binding, as evidenced by root mean square deviation (RMSD) values within a narrow range, underscoring the structural integrity of the enzyme-ligand complexes. The root mean square fluctuation (RMSF) analysis indicates consistent dynamic behavior of the MTHFD2 complex upon binding with [125I]anastrozole and [125I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[125I]anastrozole and 16.84 Å for MTHFD2-[125I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [125I]anastrozole and [125I]epirubicin complexes, respectively, highlighting crucial stabilizing interactions. The MM-PBSA calculations further endorse the thermodynamic favorability of these interactions, with binding free energies of -48.49 ± 0.11 kJ/mol for [125I]anastrozole and -43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [125I]anastrozole and [125I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [125I]anastrozole and [125I]epirubicin as MTHFD2 inhibitors, heralding a notable advancement in precision oncology tools. The data necessitate subsequent in vitro and in vivo assays to corroborate these results.
摘要：
在放射性药物的动态领域，创新靶向药物对癌症诊断和治疗至关重要.我们的研究通过评估放射性碘标记的阿那曲唑（[125I]阿那曲唑）和放射性碘标记的表柔比星（[125I]表柔比星）作为针对MTHFD2驱动的肿瘤的靶向剂的潜力来丰富这一不断发展的景观。MTHFD2在一碳代谢中至关重要，在各种癌症中显著上调，为放射性药物应用提供了一种新的靶标。通过分子对接和200ns分子动力学(MD)模拟，我们评估了[125I]阿那曲唑和[125I]表柔比星与MTHFD2的结合效率和稳定性。分子对接说明[125I]表柔比星具有-41.25kJ/mol的更好的结合自由能（ΔGbind），与[125I]阿那曲唑的-39.07kJ/mol和对照配体的-38.53kJ/mol相比，表明它对MTHFD2具有更高的亲和力。MD模拟加强了这一点，显示稳定的结合，由窄范围内的均方根偏差(RMSD)值证明，强调酶-配体复合物的结构完整性。均方根波动（RMSF）分析表明，MTHFD2复合物在与[125I]阿那曲唑和[125I]表柔比星与对照结合时具有一致的动态行为。MTHFD2-[125I]阿那曲唑的回转半径（RG）测量值为16.90µ，MTHFD2-[125I]表柔比星的回转半径为16.84µ，证实了结合后的结构破坏最小。氢键分析揭示了[125I]阿那曲唑和[125I]表柔比星复合物的两个和三个稳定氢键的平均值，分别,强调关键的稳定互动。MM-PBSA计算进一步证明了这些相互作用的热力学有利性，[125I]阿那曲唑的结合自由能为-48.49±0.11kJ/mol，MTHFD2-的结合自由能为-43.8kJ/mol。范德华和静电相互作用对[125I]阿那曲唑和[125I]表柔比星的结合亲和力的重大贡献，分别,强调了它们在靶向肿瘤成像和治疗中的潜在功效。这些计算发现为将来实验验证[125I]阿那曲唑和[125I]表柔比星作为MTHFD2抑制剂奠定了基础，预示着精密肿瘤学工具的显着进步。数据需要随后的体外和体内测定来证实这些结果。
