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

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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 led to the design of trimethoprim [an antibacterial drug] analogs with improved binding properties. Computer graphic techniques were 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 analogs were binding in the predicted manner. The C4,C6-dicarboxylic acid analog was designed to interact with Arg-57 and His-28 in the enzyme, and this analog bound 3 orders of magnitude more tightly than the parent brodimoprim.