Trends in coordination of rhenium organometallic complexes in the Protein Data Bank

Abstract

Radiopharmaceutical development has similar overall characteristics to any biomedical drug development requiring a compound's stability, aqueous solubility and selectivity to a specific disease site. However, organometallic complexes containing 188/186Re or 99mTc involve a d-block transition-metal radioactive isotope and therefore bring additional factors such as metal oxidation states, isotope purity and half life into play. This topical review is focused on the development of radiopharmaceuticals containing the radioisotopes of rhenium and technetium and, therefore, on the occurrence of these organometallic complexes in protein structures in the Worldwide Protein Data Bank (wwPDB). The purpose of incorporating the group 7 transition metals of rhenium/technetium in the protein and the reasons for study by protein crystallography are described, as certain PDB studies were not aimed at drug development. Technetium is used as a medical diagnostic agent and involves the 99mTc isotope which decays to release gamma radiation, thereby employed for its use in gamma imaging. Due to the periodic relationship among group 7 transition metals, the coordination chemistry of rhenium is similar (but not identical) to that of technetium. The types of reactions the potential model radiopharmaceutical would prefer to partake in, and by extension knowing which proteins and biomolecules the compound would react with in vivo, are needed. Crystallography studies, both small molecule and macromolecular, are a key aspect in understanding chemical coordination. Analyses of bonding modes, coordination to particular residues and crystallization conditions are presented. In our Forward look as a concluding summary of this topical review, the question we ask is: what is the best way for this field to progress?

Time-series analysis of rhenium(I) organometallic covalent binding to a model protein for drug development

“…The occupancy value of the Re bound to the His15 residue however remains the highest and is on this basis preferred to those of the aspartic acid residues. A review of reported rhenium-bound protein structures in the PDB indicated that rhenium, irrespective of oxidation state or chemical formula, has a preference for histidine coordination across a range of different proteins (Brink et al, 2022). However, note that chemical kinetic studies under non-biological conditions indicate that Re-substitution rates and water-exchange rates are found to be slightly dependant on the nature of the incoming ligand, with the softer S-bonded ligands coordinating faster than N-bonded followed by O-bonded ligands to the rhenium metal centre (Salignac et al, 2003;Grundler et al, 2006).…”

“…To circumvent this, the addition of an excess of imidazole was explored to assist in the crystallization. This arose on reviewing the crystallization conditions of all rhenium-protein structures listed in the Worldwide Protein Data Bank (wwPDB) (Burley et al, 2019;Brink et al, 2022). We noted that for many of the structures, where rhenium bound covalently to histidine, imidazole was present in the crystallization media.…”

The evolution of raw data archiving and the growth of its importance in crystallography

“…As an example, crystallography contributed to understanding the COVID-19 pandemic through its COVID-19 viral protein structures. These aspects of interoperability are discussed in more detail by Brink et al (2024) in a companion article in this IUCr 75th Committee on Data special issue.…”

“…Being a full day, it complemented the main Congress microsymposium entitled 'Raw diffraction data reuse: warts and all'. A second microsymposium of the Committee on Data as principal proposer was entitled 'Interoperability of Data and Databases' (Brink et al, 2024). We also secured a Congress keynote presented by Andy Go ¨tz of ESRF on the 'European Photon and Neutron Open Science Cloud', this being the world leading effort of this consortium of more than ten European synchrotron, neutron and X-ray laser radiation sources with raw data management and sharing.…”

Chemistry and crystal engineering

“…An intriguing example is recent work by Takiguchi et al who devised a deep learning model to determine which of 20000 metal complexes extracted from the Cambridge Structural Database (CSD) are single-molecule magnets (SMM) with 70% accuracy (Takiguchi et al, 2024). The latter article highlights the enormous value the CSD (Ferrence et al, 2023) and other databases offer so it is encouraging to see the work being done by CODATA to ensure the interoperability of crystallographic data within the FAIR principles (findable, accessible, interoperable and reusable) (Brink et al, 2024).…”