Abstract
In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antifungal Agents / chemistry
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Antifungal Agents / pharmacology*
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Antifungal Agents / toxicity
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Candida albicans / drug effects*
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Candida albicans / enzymology
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Candida albicans / growth & development
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Candida glabrata / drug effects
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Candida glabrata / enzymology
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Cell Line
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Cell Survival / drug effects
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Folic Acid Antagonists / chemistry
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Folic Acid Antagonists / pharmacology*
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Folic Acid Antagonists / toxicity
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Fungal Proteins / chemistry
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Fungal Proteins / metabolism*
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Humans
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Models, Molecular
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Molecular Structure
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Pargyline / chemistry
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Pargyline / pharmacology
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Pargyline / toxicity
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Protein Binding
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Protein Conformation
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Pyrimidines / toxicity
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Structure-Activity Relationship
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Substrate Specificity
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Tetrahydrofolate Dehydrogenase / chemistry
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Tetrahydrofolate Dehydrogenase / metabolism*
Substances
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Antifungal Agents
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Folic Acid Antagonists
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Fungal Proteins
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Pyrimidines
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2,4-diaminopyrimidine
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Pargyline
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Tetrahydrofolate Dehydrogenase