Zirconium Coordination Chemistry and its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics

In the last decade, there has been a growth in using Zirconium-89 (89 Zr) as a radionuclide in nuclear medicine for cancer diagnostic imaging and drug discovery processes. One of the most popular chelators for 89 Zr, is desferrioxamine (DFO) which acts as a hexadentate ligand. The coordination structure of the Zr4+-DFO complex has primarily been informed by DFT-based calculations which typically ignore temperature and therefore entropic and dynamic solvent effects. In this work, free energy calculations using molecular dynamics simulations, where the conformational fluctuations of both the ligand and the solvent are explicitly included, are used to compare the binding of Zr4+ cation with two different chelators, DFO and 4HMS, the latter of which has been recently proposed as a better chelator. We find that thermal induced disorder leads an open hexadentate chelate structure of Zr4+-DFO complex, leaving the Zr4+ metal exposed to the solvent. A stable coordination of Zr4+ with 4HMS, however, is formed involving both hydroxamate groups and water molecules in a more closely packed structure.