Structural characteristics of small-molecule antifolate compounds

Carl H. Schwalbe*, Vivian Cody

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Because of the importance of dihydrofolate reductase (DHFR) inhibitors in the treatment of infections and cancer, a wealth of structural information has been collected. Small-molecule crystallography has been carried out on the drugs alone or in salts, and macromolecular crystallography on the drugs bound to DHFR from a number of different species. This review provides an analysis of the small-molecule data. The natural substrates of DHFR contain the pterin (2-amino-4-oxopteridine) ring system, and the ring geometry is compared as this system is changed to the 2,4-diamino analogue found in inhibitors and/or simplified to a single ring and/or subjected to steric hindrance. Clinically useful antifolates have separate ring systems linked by three rotatable bonds as in methotrexate, or two as in trimethoprim, or one as in pyrimethamine. In the latter two cases enough structures are available to provide a clear picture of the preferred disposition(s) of rings around the linkages. Because a very important interaction between inhibitors and DHFR is a pair of hydrogen bonds from the protonated 2,4-diaminopyrimidine moiety of the inhibitor to a carboxylate anion from DHFR, its geometry in small-molecule salts with oxyanions is expressed in terms of deformations from a fiducial arrangement and also subjected to cluster analysis. Finally, the supramolecular interactions in the small-molecule structures are built up from two modules describing the interactions at the 1- and 2-positions and at the 3- and 4-positions of the 2,4-diamino- or 2-amino-4-oxopyrimidine moieties. Reassuringly for drug design, the following review will show that the molecular conformations and supramolecular interactions of inhibitors bound to DHFR match reasonably well-populated subsets found in the small-molecule context here.

Original languageEnglish
Pages (from-to)267-300
Number of pages34
JournalCrystallography Reviews
Issue number4
Publication statusPublished - 1 Oct 2006


  • Antifolate compounds
  • DHFR
  • Small-molecule crystallography


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