Trimethoprim, structure

Hagler, Structure and energetics of ligand binding to proteins Escherichia coli dihydrofolate reductase-trimethoprim, a drug-receptor system, Proteins 4 31 (1988). 

R. Beddell, J. N. Champness, D. K. Stammers, and J. Kraut, Refined crystal structure of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim, J. Biol. Chem. 260 381 (1985). 

Fig. 10 Structure and atom numbering for trimethoprim. Reprinted with permission from [75] 2005, American Chemical Society...

Fig. 3.10 Examples of isosteric binding competition. (A) ALIS-MS results for the titration of 5 pM Zap-70 by staurosporine in the presence of a 5 m concentration of its structural congener K252a and (B) titration of 5 pM DHFR with the known DHFR inhibitor trimethoprim in the presence of ligand NCD-157 at 5 pm concentration. Linear MS response ratios in these experiments are consistent with direct binding competition. (C) Compound structures.

This sol-gel procedure is an elaboration on well established entrapment methods [29], but with the added advantage of stability and better flow properties. Interestingly, none of the examples presented thus far demonstrate competitive behavior between multiple ligands (i.e. displacement) in the FAC analysis of trimethoprim and pyrimethamine a reversed order of elution based on is described, but this could simply be due to the shift towards an on-rate limited situation for higher affinity compounds, as described earlier. Erosion of dynamic competition between ligands could occur if the sol-gel allows convective mixing of the entrapped protein however the bimodal pore structure of these materials would... 

A while later, pyrimethamine (33.1.60) was suggested as a result of intensive research of antimetabolites of folic acid. Trimethoprim (33.1.51) is the result of later research. The structural similarity of these drugs with the pteridine fragment of folic acid undoubtedly determines their affinity with binding regions of dihydrofolate reductase. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Trimethoprim (Trimpex, Proloprim) is a structural analogue of the pteridine portion of dihydrofolic acid. It differs from the sulfonamides in that it acts at a second step in the folic acid synthetic pathway that is, it... 

Using a guanidino group as the seed, output structures similar to several known DHFR inhibitors were generated, such as 74 which may be compared to trimethoprim (2). 

Another dihydrofolate inhibitor trimethoprim is an important antibacterial drug, usually given together with a sulfonamide. Although it is not as close a structural analog of folic acid as is methotrexate, it is... 

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively againstM tuberculosis. It is structurally similar to /i-aminobenzoic aid (PABA) and to the sulfonamides (see Chapter 46 Sulfonamides, Trimethoprim, Quinolones). 

The crystal structures of the E. coli DHFR-methotrexate binary complex (Bolin et al., 1982), of the Lactobacillus casei (DHFR-NADPH-methotrexate ternary complex (Filman et al., 1982), of the human DHFR-folate binary complex (Oefner et al., 1988), and of the mouse (DHFR-NADPH-trimethoprim tertiary complex (Stammers et al., 1987) have been resolved at a resolution of 2 A or better. The crystal structures of the mouse DHFR-NADPH-methotrexate (Stammers et al., 1987) and the avian DHFR—phenyltriazine (Volz et al., 1982) complexes were determined at resolutions of 2.5 and 2.9 A, respectively. Recently, the crystal structure of the E. coli DHFR—NADP + binary and DHFR-NADP+-folate tertiary complexes were resolved at resolutions of 2.4 and 2.5 A, respectively (Bystroff et al., 1990). DHFR is therefore the first dehydrogenase system for which so many structures of different complexes have been resolved. Despite less than 30% homology between the amino acid sequences of the E. coli and the L. casei enzymes, the two backbone structures are similar. When the coordinates of 142 a-carbon atoms (out of 159) of E. coli DHFR are matched to equivalent carbons of the L. casei enzyme, the root-mean-square deviation is only 1.07 A (Bolin et al., 1982). Not only are the three-dimensional structures of DHFRs from different sources similar, but, as we shall see later, the overall kinetic schemes for E. coli (Fierke et al., 1987), L. casei (Andrews et al., 1989), and mouse (Thillet et al., 1990) DHFRs have been determined and are also similar. That the structural properties of DHFRs from different sources are very similar, in spite of the considerable differences in their sequences, suggests that in the absence, so far, of structural information for ADHFR it is possible to assume, at least as a first approximation, that the a-carbon chain of the halophilic enzyme will not deviate considerably from those of the nonhalophilic ones. 

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