ArticleChemical biology & drug design2011
Crystal structures of Candida albicans dihydrofolate reductase bound to propargyl-linked antifolates reveal the flexibility of active site loop residues critical for ligand potency and selectivity.
Article in Chemical biology & drug design, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 20 citations in OpenAlex.
- Benzyldimethyldodecyl Ammonium Chloride-Doped Denture-Based Resin: Impact on Strength, Surface Properties, Antifungal Activities, and In Silico Molecular Docking Analysis.Journal of functional biomaterials · 2024Article
- Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris.Acta crystallographica. Section D, Structural biology · 2023Article
- Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis.PloS one · 2016Article
- Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata.Journal of medicinal chemistry · 2014Article
- Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase.Biochemistry · 2013Article
- Structural analysis of the active sites of dihydrofolate reductase from two species of Candida uncovers ligand-induced conformational changes shared among species.Bioorganic & medicinal chemistry letters · 2013Article
- Acetylenic linkers in lead compounds: a study of the stability of the propargyl-linked antifolates.Drug metabolism and disposition: the biological fate of chemicals · 2012Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Candida albicans and Candida glabrata cause fungal bloodstream infections that are associated with significant mortality. As part of an effort to develop potent and selective antifolates that target dihydrofolate reductase (DHFR) from Candida species, we report three ternary crystal structures of C. albicans DHFR (CaDHFR) bound to novel propargyl-linked analogs. Consistent with earlier modeling results, these structures show that hydrophobic pockets in the binding site may be exploited to increase ligand potency. The crystal structures also confirm that loop residues Thr 58- Phe 66, which flank the active site and influence ligand potency and selectivity, adopt multiple conformations. To aid the development of a dual Candida spp. inhibitor, three new crystal structures of C. glabrata DHFR (CgDHFR) bound to similar ligands as those bound in the ternary structures of CaDHFR are also reported here. Loop residues 58-66 in CgDHFR and human DHFR are 1 and 3 Å closer to the folate binding site, respectively, than loop residues in CaDHFR, suggesting that a properly size ligand could be a potent and selective dual inhibitor of CaDHFR and CgDHFR.
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