Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii.
Article Details
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Graffner-Nordberg M, Kolmodin K, Aqvist J, Queener SF, Hallberg A
Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii.
J Med Chem. 2001 Jul 19;44(15):2391-402.
- PubMed ID
- 11448221 [ View in PubMed]
- Abstract
A series of lipophilic soft drugs structurally related to the nonclassical dihydrofolate reductase (DHFR) inhibitors trimetrexate and piritrexim have been designed, synthesized, and evaluated in DHFR assays, with special emphasis on the inhibition of P. carinii DHFR. The best inhibitors, encompassing an ester bond in the bridge connecting the two aromatic systems, were approximately 10 times less potent than trimetrexate and piritrexim. The metabolites were designed to be poor inhibitors. Furthermore, molecular dynamics simulations of three ligands in complex with DHFR from Pneumocystis carinii and from the human enzyme were conducted in order to better understand the factors determining the selectivity. A correct ranking of the relative inhibition of DHFR was achieved utilizing the linear interaction energy method. The soft drugs are intended for local administration. One representative ester was selected for a pharmacokinetic study in rats where it was found to undergo fast metabolic degradation to the predicted inactive metabolites.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Trimetrexate Dihydrofolate reductase Protein Humans YesInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Piritrexim Dihydrofolate reductase IC 50 (nM) 17 N/A N/A Details Piritrexim Dihydrofolate reductase IC 50 (nM) 34 N/A N/A Details Trimethoprim Dihydrofolate reductase IC 50 (nM) 2700 N/A N/A Details Trimethoprim Dihydrofolate reductase IC 50 (nM) 26800 N/A N/A Details Trimetrexate Dihydrofolate reductase IC 50 (nM) 42 N/A N/A Details Trimetrexate Dihydrofolate reductase IC 50 (nM) 10 N/A N/A Details