Computer-Aided Design of Metallopharmaceuticals: A Molecular Mechanics Force Field for Gadolinium Complexes

Abstract

The purpose of this research is to effectively and efficiently predict the geometries of gadolinium complexes that are of a size ( ~ 5 0 atoms) and which possess ligand types making them of potential interest as magnetic resonance imaging (MRI) contrast agents. This research extends a standard molecular mechanics (MM) force field for organic compounds to gadolinium complexes. Force field parameters are derived to permit modeling of prototypical hard nitrogen and oxygen ligands commonly found in lanthanide coordination chemistry. Several new ligating atom types are defined-neutral sp3 oxygen (water, alcohols, and ethers), neutral sp3 nitrogen (amines), neutral sp2 oxygen (carbonyls), neutral sp2 nitrogen (imines and pyridines), and negative oxygen (carboxylates). The new force field is generally able to predict the geometries of Gd'(Schiff base)(H20), and related complexes to within 3% of metric data (i.e., bond lengths and bond angles) as determined by X-ray crystallographic analysis. Torsional angles about individual bonds are also typically predicted to within 5, allowing one to reproduce the three-dimensional (or tertiary) structure of the Gd(II1) complexes. The use of a simple molecular mechanics force field permits the geometry optimization of these complexes to be carried out quickly by using commercially available software on a standard personal computer.