3E0B

Bacillus anthracis Dihydrofolate Reductase complexed with NADPH and 2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (UCP120B)

Summary for 3E0B

• Entry DOI: 10.2210/pdb3e0b/pdb
• Descriptor: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine, ... (4 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Bacillus anthracis
• Total number of polymer chains: 2
• Total formula weight: 41606.53

Authors

Anderson, A.C.,Beierlein, J.M.,Frey, K.M. (deposition date: 2008-07-31, release date: 2008-11-25, Last modification date: 2023-11-01)

Primary citation

Beierlein, J.M.,Frey, K.M.,Bolstad, D.B.,Pelphrey, P.M.,Joska, T.M.,Smith, A.E.,Priestley, N.D.,Wright, D.L.,Anderson, A.C.
Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase
J.Med.Chem., 51:7532-7540, 2008

PubMed 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.

PubMed: 19007108
DOI: 10.1021/jm800776a

Experimental method

X-RAY DIFFRACTION (2.25 Å)