Comparison of cyclosporin variants B-E based on their structural properties and activity in mitochondrial membranes.

Cyclosporins B, C, D, and E were characterized by NMR spectroscopy, and backbone flexibility was studied by molecular dynamics simulation. Structures of the molecules were characterized by nuclear Overhauser effect spectroscopy, which revealed that the studied peptides have many common features. Molecular dynamics simulation showed that the backbone of cyclosporin E is relatively more rigid than in other peptides. Calcium-dependent swelling of liver mitochondria under the influence of four considered compounds was also investigated. Three of them were found to have the activity similar to cyclosporin A, inhibiting opening of the mitochondrial pore at concentrations within 100-300 nM. However, cyclosporin E did not show any biological effect at concentrations up to 1 µM. Results of this study agree with the idea on the correlation between the peptide chain flexibility and its bioavailability.

Determination of preferred conformations of ibuprofen in chloroform by 2D NOE spectroscopy.

Solution of an anti-inflammatory drug ibuprofen ((RS)-2-(4-isobutylphenyl) propionic acid) in chloroform was studied by nuclear magnetic resonance spectroscopy. A set of 2D NOESY spectra was analyzed in order to obtain atom-atom distances. Since ibuprofen is known to exist as an ensemble of different conformations, these distances are averaged over the ensemble. To compare experimental and calculated distances, three models of averaging were concerned. Our data allowed to determine the dominant conformers of ibuprofen dissolved in chloroform. The population of conformers in the saturated solution leads to a certain crystal morphology formed within the nucleation process. Observed and calculated (13)C chemical shifts (at the DFT/B3LYP/6-311+G(2d,p) level) were in good agreement.