Bioinformatic analysis of glycogen synthase kinase 3: Human versus parasite kinases

Abstract

Objective. Glycogen synthase kinase 3 (GSK-3) is a promising target for the treatment of various human diseases such as type 2 diabetes, Alzheimer's disease and inflammation. Successful inhibition of the homologues of this kinase in Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani makes the kinase an attractive target for the treatment of malaria, trypanosomiasis and leishmaniasis, respectively. The aim of this work was to compare the binding sites of the GSK-3 kinases of different parasites and to analyse them as possible targets for therapeutic compounds. Methods. Both a sequence alignment and homology models of the structure of 21 different GSK-3 homologues belonging to mammals, insects, pathogenic fungi, nematodes, trematodes and protozoa have been analysed, 17 of them being studied for the first time. Results. The structure of the kinases and, in particular, their binding sites, were found to be rather conserved, possessing small insertions or deletions and conserved amino acid substitutions. Nevertheless, the kinases of most species of parasite did have some amino acid differences from the human kinase, which could be exploited for the design of selective drugs. Conclusion. Comparison of the human and parasite GSK-3 ATP binding site models has shown that the development of selective drugs affecting parasite GSK-3 is possible. Known inhibitors of human GSK-3 can also be used as starting scaffolds for the search for drugs acting against parasitic diseases. Copyright © Cambridge University Press 2011.