Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures.
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 reductase without inhibiting host glutathione reductase. This was confirmed by testing 30 phenothiazine and tricyclic antidepressants, of which clomipramine was found to be the most potent, with a K(i) of 6 microM, competitive with respect to trypanothione. Many of these compounds have been noted previously to have anti-trypanosomal and anti-leishmanial activity and thus they can serve as lead structures for rational drug design.
Benson
T J
TJ
Department of Pharmacy, University of Manchester, U.K.
McKie
J H
JH
Garforth
J
J
Borges
A
A
Fairlamb
A H
AH
Douglas
K T
KT
D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D010640:Phenothiazines; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D013095:Spermidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000201:enzymology
D000981:Antiprotozoal Agents; D014150:Antipsychotic Agents; D010640:Phenothiazines; D011994:Recombinant Proteins; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D013095:Spermidine