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 Vol. 49; no. 24; pp. 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:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 30-11-2006
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 Molecular structure Enzyme Escherichia coli Enzyme inhibitor Inhibitor enzyme complex Competitive inhibition X ray diffraction In vitro Modeling Antimetabolic Structure activity relation Molecular model Bacteria Oxidoreductases Dihydrofolate reductase Enterobacteriaceae Crystalline structure
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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.
Bibliography:	istex:C96987D4A6BCE2EF49E8D6283B046446ED4B8562 ark:/67375/TPS-BMQJX73R-0 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm060570v