O

NADPH NADP+

FIGURE 2.28 Reaction catalyzed by DHFR.

NADPH NADP+

FIGURE 2.28 Reaction catalyzed by DHFR.

It catalyzes the transfer of the pro-R hydrogen of the C-4 position of the dihydro-pyridine ring in the cofactor onto the C=N double bonds of folic acid and dihydrofolic acid (Fig. 2.28).

The most potent inhibitors of DHFR are folic acid analogs that differ from the natural ligand in that they bear a 2,4-diaminopyrimidine unit, as exemplified by aminopterin (AM) and methotrexate (MTX, amethopterin). The inhibitors in which the side chain ends in a glutamic acid residue, as in folic acid, are known as classical antifolates. Other inhibitors with lipophilic substituents are known as nonclassical antifolates.

5.1. Classical DHFR inhibitors

MTX and AM were designed by replacing an OH group at C-4 of the natural substrate (DHF) by an amino group. The implicit assumption was that the two ligands would bind similarly and that the 4-amino group of MTX would go to the position in the binding site normally occupied by the DHF oxygen. However, when X-ray diffraction structures of DHFR with DHF and MTX were obtained, different binding modes were observed, with the aminopteridine ring of MTX flipped 180° about the C6-CH2NHR bond in regard to that of DHF (Fig. 2.29).

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