Computational Pipeline for the Design and In Silico Evaluation of Novel Hydroxamate-Macrocyclic Hybrid Chelators for Zirconium-89 and Actinium-225 Radiopharmaceuticals

The advancement of radiopharmaceutical agents for theranostic applications is constrained by the limited availability of high-performance chelators capable of forming thermodynamically stable and kinetically inert complexes with medically relevant radiometals. This is particularly challenging for positron emitters like Zirconium-89 (89Zr) for immuno-PET imaging and alpha emitters such as Actinium-225 (225Ac) for targeted alpha therapy (TAT). Current clinical standards like Desferrioxamine B (DFO) and DOTA suffer from known issues, including insufficient in vivo stability and suboptimal chelation efficiency for these specific radionuclides. In this study, a comprehensive computational workflow integrating Density Functional Theory (DFT), Molecular Dynamics (MD) simulations, and in silico ADME/toxicity prediction was employed to design and evaluate novel chelator scaffolds. These included scaffolds based on hydroxamate, macrocyclic, and a novel hybrid framework combining features of both. DFT calculations at the B3LYP/LANL2DZ level predicted that the hybrid scaffold exhibits superior binding energies with both 89Zr (− 168.7 kcal/mol) and 225Ac (− 198.9 kcal/mol), surpassing the performance of the other two scaffolds. The exceptional thermodynamic stability of the hybrid complex was corroborated by 100 ns MD simulations, which demonstrated remarkable kinetic inertness with minimal structural deviation. In silico ADME and toxicity profiling further indicated favorable drug-likeness and a very low acute toxicity profile for the hybrid chelator. These findings establish the hydroxamate-macrocyclic hybrid as a highly promising candidate for experimental validation and validate the efficacy of an integrated computational approach for the rational design of next-generation radiopharmaceutical agents.