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Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues.

Abstract:

By the use of molecular models of Escherichia coli dihydrofolate reductase (DHFR), analogues of trimethoprim (TMP) were designed which incorporated various 3'-carboxyalkoxy moieties in order to acquire ionic interactions with positively charged active-site residues. Certain of these compounds have shown exceptionally high affinity for this enzyme. For example, the 3'-(carboxypentyl)oxy analogue was found to be 55-fold more inhibitory than TMP toward E. coli DHFR (Ki = 0.024 nM vs. 1.32 nM for...

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Publication status:
Published

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Publisher copy:
10.1021/jm00381a008

Authors


Kuyper, LF More by this author
Baccanari, DP More by this author
Beddell, CR More by this author
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Journal:
Journal of medicinal chemistry
Volume:
28
Issue:
3
Pages:
303-311
Publication date:
1985-03-05
DOI:
EISSN:
1520-4804
ISSN:
0022-2623
URN:
uuid:d914a672-05e9-4b4d-81a1-6f43631d8d76
Source identifiers:
72666
Local pid:
pubs:72666

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