Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.

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Liu J, Bolstad DB, Smith AE, Priestley ND, Wright DL, Anderson AC

Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.

Chem Biol. 2008 Sep 22;15(9):990-6. doi: 10.1016/j.chembiol.2008.07.013.

PubMed ID
18804036 [ View in PubMed
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Abstract

Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamineDihydrofolate reductaseIC 50 (nM)1280N/A25Details
TrimethoprimDihydrofolate reductaseIC 50 (nM)340000N/A25Details