ArticleJournal of medicinal chemistry2010
Targeted mutations of Bacillus anthracis dihydrofolate reductase condense complex structure−activity relationships.
Article in Journal of medicinal chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 18 citations in OpenAlex.
- Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning.Journal of chemical theory and computation · 2021Article
- Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata.Journal of medicinal chemistry · 2014Article
- The structure and competitive substrate inhibition of dihydrofolate reductase from Enterococcus faecalis reveal restrictions to cofactor docking.Biochemistry · 2014Article
- Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery.Antibiotics (Basel, Switzerland) · 2014Review
- Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase.Biochimica et biophysica acta · 2013Article
- Synthesis and biological activity of substituted 2,4-diaminopyrimidines that inhibit Bacillus anthracis.European journal of medicinal chemistry · 2012Article
- Role of glutamate 64 in the activation of the prodrug 5-fluorocytosine by yeast cytosine deaminase.Biochemistry · 2012Article
- Antifolate agents: a patent review (2006 - 2010).Expert opinion on therapeutic patents · 2011Review
- New developments in vaccines, inhibitors of anthrax toxins, and antibiotic therapeutics for Bacillus anthracis.Current medicinal chemistry · 2011Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.