title: 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 TMP). X-ray crystallographic studies of E. coli DHFR in binary complexes with TMP and two members of this acid-containing series of compounds defined the binding of these inhibitors and showed the carboxyl group of the latter two inhibitors to be ionically bound to Arg-57. These observations were in agreement with postulated binding modes that were based on receptor modeling.
mesh_terms: D001665:Binding Sites; D005493:Folic Acid Antagonists; D007700:Kinetics; D008727:Methotrexate / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D005493:Folic Acid Antagonists; D014295:Trimethoprim; D008727:Methotrexate