A proton NMR study of the interactions and conformations of rationally designed brodimoprim analogs in complexes with Lactobacillus casei dihydrofolate reductase

Authors:
  • BBB. Birdsall
    B. Birdsall
  • JFJ. Feeney
    J. Feeney
  • CPC. Pascual
    C. Pascual
  • GRG. C. K. Roberts
    G. C. K. Roberts
  • IKI. Kompis
    I. Kompis
  • RTR. L. Then
    R. L. Then
  • KMK. Mueller
    K. Mueller
  • AKA. Kroehn
    A. Kroehn
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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.