title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Chemistry, Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Osolodkin
authors.affiliation: Institute of General Genetics RAS, Gubkin street 3, Moscow 119991, Russia.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Zakharevich
authors.affiliation: Department of Chemistry, Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Palyulin
authors.affiliation: Institute of General Genetics RAS, Gubkin street 3, Moscow 119991, Russia.
authors.forename: Valery N
authors.initials: VN
authors.lastname: Danilenko
authors.affiliation: Department of Chemistry, Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia.
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Zefirov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry; D001665:Binding Sites; D019295:Computational Biology; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry*; D006801:Humans; D007893:Leishmania donovani / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010271:Parasites / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014346:Trypanosoma brucei brucei / Q000201:enzymology
chemical_list: D000977:Antiparasitic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D038362:Glycogen Synthase Kinase 3