High throughput screening identifies novel inhibitors of Escherichia coli dihydrofolate reductase that are competitive with dihydrofolate.
This communication describes the high-throughput screen of a diverse library of 50,000 small molecules against Escherichia coli dihydrofolate reductase to detect inhibitors. Sixty-two compounds were identified as having significant inhibitory activity against the enzyme. Secondary screening of these revealed twelve molecules that were competitive with dihydrofolate, nine of which have not been previously characterized as inhibitors of dihydrofolate reductase. These novel molecules ranged in potency (K(i)) from 26 nM to 11 microM and may represent fresh starting points for new small molecule therapeutics directed against dihydrofolate reductase.
Zolli-Juran
Michela
M
McMaster HTS Lab, Department of Biochemistry, McMaster University, Hamilton, ON, Canada L8N 3Z5.
Cechetto
Jonathan D
JD
Hartlen
Rebecca
R
Daigle
Denis M
DM
Brown
Eric D
ED
D001667:Binding, Competitive / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D019151:Peptide Library; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*
D005493:Folic Acid Antagonists; D007202:Indicators and Reagents; D019151:Peptide Library; C010920:dihydrofolate; D009249:NADP; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase