Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.
Article Details
- CitationCopy to clipboard
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]
- 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
Drug Target Property Measurement pH Temperature (°C) 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine Dihydrofolate reductase IC 50 (nM) 1280 N/A 25 Details Trimethoprim Dihydrofolate reductase IC 50 (nM) 340000 N/A 25 Details