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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.

Paulsen JL, Bendel SD, Anderson AC
Chem Biol Drug Des 78 505-12 (2011)
Related entries: 3qlr, 3qls, 3qlw, 3qly, 3qlz

Cited: 8 times
EuropePMC logo PMID: 21726415

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.

Articles - 3qlx mentioned but not cited (2)

  1. Structural analysis of the active sites of dihydrofolate reductase from two species of Candida uncovers ligand-induced conformational changes shared among species. Paulsen JL, Viswanathan K, Wright DL, Anderson AC. Bioorg Med Chem Lett 23 1279-1284 (2013)
  2. 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. Paulsen JL, Bendel SD, Anderson AC. Chem Biol Drug Des 78 505-512 (2011)


Articles citing this publication (6)

  1. Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase. Lamb KM, G-Dayanandan N, Wright DL, Anderson AC. Biochemistry 52 7318-7326 (2013)
  2. Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata. G-Dayanandan N, Paulsen JL, Viswanathan K, Keshipeddy S, Lombardo MN, Zhou W, Lamb KM, Sochia AE, Alverson JB, Priestley ND, Wright DL, Anderson AC. J Med Chem 57 2643-2656 (2014)
  3. Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis. Hajian B, Scocchera E, Keshipeddy S, G-Dayanandan N, Shoen C, Krucinska J, Reeve S, Cynamon M, Anderson AC, Wright DL. PLoS One 11 e0161740 (2016)
  4. Acetylenic linkers in lead compounds: a study of the stability of the propargyl-linked antifolates. Zhou W, Viswanathan K, Hill D, Anderson AC, Wright DL. Drug Metab Dispos 40 2002-2008 (2012)
  5. Target Abundance-Based Fitness Screening (TAFiS) Facilitates Rapid Identification of Target-Specific and Physiologically Active Chemical Probes. Butts A, DeJarnette C, Peters TL, Parker JE, Kerns ME, Eberle KE, Kelly SL, Palmer GE. mSphere 2 e00379-17 (2017)
  6. Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris. Kirkman T, Sketcher A, de Morais Barroso V, Ishida K, Tosin M, Dias MVB. Acta Crystallogr D Struct Biol 79 735-745 (2023)


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