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 ([(125)I]anastrozole) and radioiodinated epirubicin ([(125)I]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 [(125)I]anastrozole and [(125)I]epirubicin with MTHFD2. Molecular docking illustrates that [(125)I]epirubicin has a superior binding free energy (∆G(bind)) of -41.25 kJ/mol compared to -39.07 kJ/mol for [(125)I]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 [(125)I]anastrozole and [(125)I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[(125)I]anastrozole and 16.84 Å for MTHFD2-[(125)I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [(125)I]anastrozole and [(125)I]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 [(125)I]anastrozole and -43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [(125)I]anastrozole and [(125)I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [(125)I]anastrozole and [(125)I]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.