Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase.
There is an urgent need for the development of new drugs to treat Chagas' disease, which is caused by the protozoan parasite Trypanosoma cruzi. The enzyme dihydrofolate reductase (DHFR) has been a very successful drug target in a number of diseases and we decided to investigate it as a potential drug target for Chagas' disease. A homology model of the enzyme was used to search the Cambridge Structural Database using the program DOCK 3.5. Compounds were then tested against the enzyme and the whole parasite. Compounds were also screened against the related parasite, Trypanosoma brucei.
Zuccotto
F
F
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Zvelebil
M
M
Brun
R
R
Chowdhury
S F
SF
Di Lucrezia
R
R
Leal
I
I
Maes
L
L
Ruiz-Perez
L M
LM
Gonzalez Pacanowska
D
D
Gilbert
I H
IH
D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D019992:Databases as Topic; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D051379:Mice; D009132:Muscles / Q000166:cytology; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase