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Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover(More)
Trypanothione reductase, an essential component of the anti-oxidant defences of parasitic trypanosomes and Leishmania, differs markedly from the equivalent host enzyme, glutathione reductase, in the binding site for the disulphide substrate. Molecular modelling of this region suggested that certain tricyclic compounds might bind selectively to trypanothione(More)
Trypanothione reductase, the enzyme which in trypanosomal and leishmanial parasites catalyses the reduction of trypanothione disulphide to the redox-protective dithiol and has been identified as a potential target for rational antiparasite drug design, has been found to be strongly inhibited by tricyclic compounds containing the saturated dibenzazepine(More)
By introducing cationic charge sites novel peptide lead inhibitor structures for trypanothione reductase have been designed using molecular modelling methods. The inhibitors showed reversible, linear competitive inhibition and the strongest peptide inhibitor to date was found to be N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-β-naphthylamide with a Ki value of(More)
Kinetic data for alternative substrates of recombinant trypanothione reductase from Trypanosoma cruzi were measured for a series of N-substituted-L-cysteinylglycyl-3-dimethylaminopropylamides, in which the cysteine N-substituent was either a variant of the benzyloxycarbonyl group or was L-phenylalanine or L-tryptophan. Replacing the benzylic ether oxygen(More)
The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the activesites of TR and human GR, subsequently confirmed by the TR crystal(More)
We have developed a robot controller based upon a neural implementation of Norman and Shallice's model of executive attentional control in humans. A simulation illustrates how atten-tional control leads to the suppression of action selection errors in neurally controlled robots. A related demonstration illustrates how lesioning of the control architecture(More)
Behaviour based robots have problems related to inappropriate behaviours expressed by the machines. We identify two classes of problem, capture errors and perseverative behaviour which can cause a machine to fail to meet its real-time goals. We suggest that these errors may be moderated or eliminated by the use of an executive or Supervisory Attentional(More)