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A 1H NMR study of the interactions and conformations of rationally designed brodimoprim analogues in complexes with Lactobacillus casei dihydrofolate reductase.

Abstract：

:A consideration of the detailed structural information available from X-ray crystallographic and NMR studies on complexes of dihydrofolate reductase with inhibitors has led to the design of trimethoprim analogues with improved binding properties. Computer graphic techniques have been used to predict which substituent groups were required at the 3'-O position of brodimoprim (2,4-diamino-5-(3,5-dimethoxy-4-bromobenzyl)pyrimidine) to make additional interactions with the enzyme. NMR spectroscopy provided a convenient method of assessing if the analogues were binding in the predicted manner. On the basis of this approach, the C4,C6-dicarboxylic acid analogue IX was designed to interact with Arg-57 and His-28 in the enzyme, and this analogue was found to bind 3 orders of magnitude more tightly than the parent brodimoprim.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Birdsall B,Feeney J,Pascual C,Roberts GC,Kompis I,Then RL,Müller K,Kroehn A

doi

10.1021/jm00378a025

subject

Has Abstract

pub_date

1984-12-01 00:00:00

pages

1672-6

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

27

pub_type

杂志文章

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