A 2.13 Å Structure of E. coli Dihydrofolate Reductase Bound to a Novel Competitive Inhibitor Reveals a New Binding Surface Involving the M20 Loop Region

Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (compound 1) as the correct structure of the previously reported...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-11, Vol.49 (24), p.6977-6986
Main Authors: Summerfield, Rachael L, Daigle, Denis M, Mayer, Stanislas, Mallik, Debasis, Hughes, Donald W, Jackson, Sean G, Sulek, Margaret, Organ, Michael G, Brown, Eric D, Junop, Murray S
Format: Article
Language:English
Subjects:
Binding Sites
Biological and medical sciences
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Escherichia coli - enzymology
Folic Acid Antagonists - chemical synthesis
Folic Acid Antagonists - chemistry
Guanidines - chemistry
Medical sciences
Methotrexate - chemistry
Miscellaneous
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase - chemistry
Trimethoprim - chemistry
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Summary:Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (compound 1) as the correct structure of the previously reported DHFR inhibitor 1,4-bis-{(iminothioureidomethyl)aminomethyl}-3,6-dimethyl-benzene (compound 2). The fact that compound 1 has an uncharacteristic structure for DHFR inhibitors, and an affinity (K I of 11.5 nM) comparable to potent inhibitors such as methotrexate and trimethoprim, made this inhibitor of interest for further analysis. We have conducted a characterization of the primary interactions of compound 1 and DHFR using a combination of X-ray structure and SAR analysis. The crystal structure of E. coli DHFR in complex with compound 1 and NADPH reveals that one portion of this inhibitor exploits a unique binding surface, the M20 loop. The importance of this interface was further confirmed by SAR analysis and additional structural characterization.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060570v