Rational drug design using trypanothione reductase as a target for anti-trypanosomal and anti-leishmanial drug leads.
The parasite enzyme trypanothione reductase has been used as a target for rational drug design against trypanosomiasis and leishmaniasis in a number of laboratories. In this article the biochemical basis for its selection as a target is reviewed. The relevant structural aspects of the target are then compared with the homologous structure found in the mammalian hosts to indicate the molecular basis by which selective toxicity is likely to be achieved. An overview of known classes of inhibitors is provided, preparatory to a detailed coverage of approaches that have been taken to obtaining strong, selective inhibitors and the steps taken in the process of the initial discovery of tricyclic structures by interactive molecular graphics ligand design are outlined. Recent quantitative docking approaches which have been applied to this system are also described. Finally, the biological data of the activity against the various parasitic forms in vitro and in vivo are summarised.
Austin
S E
SE
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
Khan
M O
MO
Douglas
K T
KT
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000502:physiology; D007099:Imipramine / Q000494:pharmacology; D007896:Leishmaniasis / Q000188:drug therapy; D008954:Models, Biological; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010640:Phenothiazines / Q000494:pharmacology; D011528:Protozoan Infections / Q000188:drug therapy*; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013095:Spermidine / Q000031:analogs & derivatives* / Q000502:physiology; D014352:Trypanosomiasis / Q000188:drug therapy
D018759:Adrenergic Uptake Inhibitors; D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D010640:Phenothiazines; C044809:trypanothione; D010088:Oxidoreductases; D005978:Glutathione; D007099:Imipramine; D013095:Spermidine