Dihydrofolate reductase inhibition

AJ Hopfinger. A QSAR investigation of dihydrofolate reductase inhibition by Baker triazmes based upon molecular shape analysis. I Am Chem Soc 102 7196-7206, 1980. 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Methotrexate is a folic acid analogue. Its mechanism of action is based on the inhibition of dihydrofolate reductase. Inhibition of dihydrofolate reductase leads to depletion of the tetrahydrofolate cofactors that are required for the synthesis of purines and thymidylate (see Fig. 2). Enzymes that are required for purine and thymidylate synthesis are also directly inhibited by the polyglutamates of methotrexate which accumulate with dihydrofolate reductase inhibition. The mechanisms that can cause resistance include decreased transport of methotrexate into the tumor cells, a decreased affinity of the antifolate for dihydrofolate reductase, increased concentrations of intracellular dihydrofolate reductase and decreased thymidylate synthetase activity. 

Ghose, A.K. and Crippen, G.M. (1983). Combined Distance Geometry Analysis of Dihydrofolate Reductase Inhibition by Quinazolines and Triazines. J.Med.Chem.,26, 996-1010. 

Hopfinger, A.J. (1980). A QSAR Investigation of Dihydrofolate Reductase Inhibition by Baker Triazines Based upon Molecular Shape Analysis. J.Am.Chem.Soc., 102, 7196-7206. 

Sturtz. G.. Guillamot, G., Bourdeaux, M., and Chauvet, M., Amethopterine (methotrexate) phosphonoglutamic acid analogs. Part 2. Dihydrofolate reductase inhibition, Eur. J. Med. Chem. Chim. Ther.. 19, 274, 1984. 

Mattioni, B.E. and Jurs, P.C. (2003) Prediction of dihydrofolate reductase inhibition and selectivity using computational neural networks and linear discriminant analysis. /. Mol. Graph. Model., 21, 391-419. 

Table 7-4. Selectivity of Dihydrofolate Reductase Inhibition (nM Concentration for 50% Inhibition)...

Garg and Achenie also demonstrated a reasonable approach to the solution of the I-QSAR problem in 2001. " ° Taking a target scaffold of an antifolate molecule for dihydrofolate reductase inhibition, these authors generated a QSAR for both activity and selectivity. They solved the I-QSAR problem to maximize selectivity through changing substitutents on the scaffold, subject to a constraint of a threshold activity. Finally, a work by Skvortsova, et al. " from 2003 demonstrated that the I-QSAR problem could be solved for the Hosoya index plus constraints on the number of carbon atoms for a system of 78 hydrocarbons. 

QSAR Study of Dihydrofolate Reductase Inhibition with Models Based on HFGs... 

A. J. Hopfinger, Arcfi. Biochem. Biophys., 206,153 (1981). A General QSAR for Dihydrofolate Reductase Inhibition by 2,4-Diaminotriazines Based upon Molecular Shape Analysis. 

Dihydrofolate reductase inhibition (di-2,4-NH - 1 6 pyrimidines, 5-subst.,aliphatic, cycloaliphatic 11 0.937... 

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