Dihydrofolate reductase inhibitors analysis

GM Crippen. Quantitative structure-activity relationships by distance geometry Systematic analysis of dihydrofolate reductase inhibitors. I Med Chem 23 599-606, 1980. 

Crippen, G.M. (1980). Quantitative Structure-Activity Relationships by Distance Geometry Systematic Analysis of Dihydrofolate Reductase Inhibitors. J.Med.Chem.,23,599-606. 

Hopfinger, A.J. (1983). Theory and Application of Molecular Potential Energy Fields in Molecular Shape Analysis A Quantitative Structure-Activity Relationship Study of 2,4-Diamino-5-benzylpyrimidines as Dihydrofolate Reductase Inhibitors. J.Med.Chem.,26, 990-996. 

Hopfinger, A.J. (1983) Theory and application of molecular potential energy fields in molecular shape analysis a quantitative structure-activity relationship study of 2,4-diamino-5-benzylpyrimidines as dihydrofolate reductase inhibitors. J. Med. Chem., 26,... 

Mabilia, M., Pearlstein, R.A. and Hopfinger, A.J. (1985) Molecular shape analysis and energetics-based intermolecular modelling of benzylpyrimidine dihydrofolate reductase inhibitors. Eur. j. Med. Chem., 20, 163-174. 

Santos-Filho. O.A., Mishra, R.K and Hopfinger, A.J. (2001) Free energy force field (FEFF) 3D-QSAR analysis of a set of Plasmodium falciparum dihydrofolate reductase inhibitors. J. Comput. Aid. Mol Des., 15. 787-810. 

M. Mabilia, R. A. Pearlstein, and A. J. Hopfinger, Eur. J. Med. Chem., 20, 16.3 (1985). Molecular Shape Analysis and Enei ics-Based Intermolecular Modelling of Benzylpyri-midine Dihydrofolate Reductase Inhibitors. 

Crystallographic analysis has been used quite effectively to solidify structural determinations. Several examples include dihydrofolate reductase complexes , nucleosides <1999AXC1335, 1999AXC1560>, zopi-clone <2001CC2204>, and immucillin inhibitors <2003BBR917>. 

Some of the structural properties which have been ascribed to DA receptors appear to deserve attention for their heuristic value, but painfully few should engender much confidence in their reality. A sobering lesson is available from analysis of complexes of dihydrofolate reductase (], 8). Methotrexate is a very close analog of folic acid and is a potent inhibitor of the enzyme, but it is now almost certain that these ligands bind in the enzyme active site in aspects differing by a rota-... 

MOE assigns a value of 1 or -1 for chiral molecules and zero for achiral molecules. DAPPER, was developed with this in mind and therefore can easily incorporate different conformation search techniques and chirahty metrics. A new chirality measure provides a quantitative description of the overaU chirahty of a given conformation of a molecule without assigning values to individual atoms. In this article, they discuss the analysis of several implementations of various conformation search techniques, a novel chirahty metric, and their incorporation into DAPPER with validation on three standard medicinal chemistry data sets (dihydrofolate reductase, angiotensin converting enzyme, acetylchohn-esterase). They have demonstrated clear predictive power in the case of 20 DHFR inhibitors [48]. 

Burchall, J. J., and Hitchings, G. H., Inhibitor binding analysis of dihydrofolate reductases from various species. Mol. Pharmacol. 1, 126-136 (1965). 

Another enzyme for which X-ray diffraction studies have aided in an analysis of the mode of action is the enzyme dihydrofolate reductase. This catalyzes the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential coenzyme used in the synthesis of thymidylate, inosinate, and methionine. The antitumor agent methotrexate is a powerful inhibitor of dihydrofolate reductase, causing, on binding, a cellular deficiency of thymidylate (the cause of its antitumor activity). The crystal structures of the enzyme from two bacterial sources—Escherichia coli and Lactobacillus casei—and from chicken liver have been studied (88-90). Both the E. coli and L casei enzymes have been studied as complexes with methotrexate bound at the active site, and, in the case of the . casei enzyme, the cofactor, NADPH, was also present. 

X-ray diffraction analysis of dihydrofolate reductase (DHFR), co-crystal-lized with methotrexate, has shed much light on the action of this inhibitor. This work, one of the earliest visualizations of a drug interacting with its receptor (Matthews etal., 1977), has since been refined to the remarkably clear resolution of 1.7 A (Bolin et al., 1982). A typical diagram of DHFR, its coenzyme (NADPH), and methotrexate is shown in Fig. 9.4. The enzyme depicted there is from Lactobacillus casei and the same authors also report on DHFR (with cocrystallized methotrexate) from the bacterium E. colt. However, they have not been able to co-crystallize methotrexate with DHFR from any vertebrate source. 

A Molecular Shape Analysis and Quantitative Structure-Activity Relationship Investigation of Some Triazine-Antifiilate Inhibitors of Leishmania major Dihydrofolate Reductase. 

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