Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase.

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Beierlein JM, Frey KM, Bolstad DB, Pelphrey PM, Joska TM, Smith AE, Priestley ND, Wright DL, Anderson AC

Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase.

J Med Chem. 2008 Dec 11;51(23):7532-40. doi: 10.1021/jm800776a.

PubMed ID

19007108 [ View in PubMed

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Abstract

Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 A resolution. The structure reveals several features that can be exploited for further development of this lead series.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Dihydrofolate reductase	Q81R22	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine	Dihydrofolate reductase	IC 50 (nM)	1280	7	25	Details
Trimethoprim	Dihydrofolate reductase	IC 50 (nM)	120000	7	25	Details