Abstract
Multiple possibilities for the coordination of fac-[Re(CO)3(H2O)3]+ to a protein have been determined and include binding to Asp, Glu, Arg and His amino-acid residues as well as to the C-terminal carboxylate in the vicinity of Leu and Pro. The large number of rhenium metal complex binding sites that have been identified on specific residues thereby allow increased target identification for the design of future radiopharmaceuticals. The core experimental concept involved the use of state-of-art tuneable synchrotron radiation at the Diamond Light Source to optimize the rhenium anomalous dispersion signal to a large value (f'' of 12.1 electrons) at its LI absorption edge with a selected X-ray wavelength of 0.9763 Å. At the Cu Kα X-ray wavelength (1.5418 Å) the f'' for rhenium is 5.9 electrons. The expected peak-height increase owing to the optimization of the Re f'' was therefore 2.1. This X-ray wavelength tuning methodology thereby showed the lower occupancy rhenium binding sites as well as the occupancies of the higher occupancy rhenium binding sites.
Highlights
Rhenium-188/186 and technetium-99m tricarbonyl complexes have shown much potential as therapeutic and diagnostic radiopharmaceuticals
We report here the coordination of multiple fac-[Re(CO)3]+ complex fragments to a protein that was selected to provide a full range of exposed amino acids. Both monodentate and bidentate complex coordination were observed to the aspartic acid, glutamic acid, arginine, leucine, proline and histidine residues, indicating preferential binding to neutral and anionic N and O atom donors with pKa values varying from 3.71 to 4.15 (Cantor & Schimmel, 1980; Betts & Russell, 2003). These structural observations are critical for the development of radiopharmaceutical drug design using the fac-[M(CO)3]+ radionuclide core (Alberto et al, 1995, 1998, 2001), in particular considering the fragment-based drugdesign (FBDD) method (Joseph-McCarthy et al, 2014; Erlanson, 2012; Murray et al, 2012), as specific protein–ligand binding of low-molecular-weight fragments can be exploited to derive a model for possible drug-like lead compounds
We provide the three-dimensional information required for new drug-lead development for rhenium-compound interactions with a wide range of amino acids, which was derived from X-ray crystallography supplemented with extensive analysis of the Cambridge Structural Database (CSD; Allen, 2002) and was supported by the precise distance measurements which can be obtained by using the diffraction precision index (DPI; Gurusaran et al, 2014; Kumar et al, 2015)
Summary
Rhenium-188/186 and technetium-99m tricarbonyl complexes have shown much potential as therapeutic and diagnostic radiopharmaceuticals. We report here the coordination of multiple fac-[Re(CO)3]+ complex fragments to a protein that was selected to provide a full range of exposed amino acids Both monodentate and bidentate complex coordination were observed to the aspartic acid, glutamic acid, arginine, leucine, proline and histidine residues, indicating preferential binding to neutral and anionic N and O atom donors with pKa values varying from 3.71 to 4.15 (Cantor & Schimmel, 1980; Betts & Russell, 2003). The results obtained here in this study, whereby rhenium coordination is observed to aspartic acid, glutamic acid, arginine and leucine residues, arising from the technical innovation of using tuned X-ray wavelengths to improve the detectability of Re-atom binding, opens new alternatives for preferential binding other than to an imidazole moiety of histidine alone
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
