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

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Abstract
By the use of molecular models of Escherichia coli dihydrofolate reductase (DHFR), analogs 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 showed exceptionally high affinity for this enzyme. The 3''-(carboxypentyl)oxy analog was 55-fold more inhibitory than TMP toward E. coli DHFR (Ki = 0.024 nM vs. 1.32 nM for TMP). X-ray crystallographic studies of E. coli DHFR in binary complexes with TMP and 2 members of this acid-containing series of compounds defined the binding of these inhibitors and showed the carboxyl group of the latter 2 inhibitors to be ionically bound to Arg-57. These observations were in agreement with postulated binding modes that were based on receptor modeling.