Structural highlights
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.,Liu J, Bolstad DB, Smith AE, Priestley ND, Wright DL, Anderson AC Chem Biol. 2008 Sep 22;15(9):990-6. PMID:18804036[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. PMID:18804036 doi:S1074-5521(08)00280-9
