In Silico Studies, partition coefficients and tissue permeability of Cu(II)Tripeptide species as Potential Anti-Inflammatory Drugs

Abstract

Rheumatoid arthritis (RA) is a form of chronic inflammation, a systemic autoimmune disorder that destroys synovial joints. The cause of RA is still unknown, and at present and there is no cure. RA is one of the most common types of chronic inflammatory polyarthritis. It represents a significant health burden with an approximately 1% prevalence worldwide. It mainly affects women, two times more than men. Copper complexes were used in the 1940's to 1970's for the treatment of the inflammation associated with RA. The ligands chosen were sarcosyl-L-histidyl-L-lysine (Sar-His-Lys), sarcosyl-L-lysyl-L-histidine (Sar-Lys His), sarcosyl-L-histidyl-L-histidine (Sar-His-His), sarcosyl-L-lysyl-L-lysine (Sar Lys-Lys), sarcosyl-L-glycyl-L-histidine (Sar-Gly-His) and sarcosyl-L-leucyl phenylalanine (Sar-Leu-Phe). Our previous studies have shown equilibrium constants of H+ , Cu(II), Ni(II) and Zn(II) with these tripeptides and the structures of the complex species were investigated using UV-Vis, ESR and 1H NMR spectroscopy. An objective of the study was to increase the available pool of copper in vivo. This was evaluated using a computer model of blood plasma, which considers competition with endogenous metal ions and ligands. It is particularly important that the ligands were evaluated using the Evaluation of Constituent Concentrations in Large Equilibrium (ECCLE) system, an in vivo speciation model of blood plasma. Dermal absorption is the preferred method of administration, and so this study used partition coefficients and tissue permeability studies to assess the bioavailability of the different complexes. Based on the results of this study, Sar Lys-His and Sar-Gly-His have a higher mobilising capacity than all the other tripeptides.