Binding of methotrexate

The above model was used to study the binding of methotrexate, and analogues of it, to wild-type and mutant forms of human dihydrofolate reductase (DHFR).29 This turned out to be a particularly difficult test because of the three ionized groups of methotrexate. The overall electrostatic interactions of this inhibitor amount to around -500 kcal/mol and MD trajectories of length more than a ns were required in order to get average... 

Maia, M.B., Saivin, S., Chatelut, E., Malmary, M.F. and Houin, G. (1996) In vitro and in vivo protein binding of methotrexate assessed by microdialysis. International Journal of Clinical Pharmacology and Therapeutics, 34, 335-341. 

The importance of non-polar residues to binding of methotrexate has also been examined, both by site-specific mutation (Taira and Benkovic, 1988)... 

METHOTREXATE ANTIGOUT DRUGS -PROBENECID t methotrexate levels Probenecid 1 elimination of methotrexate renally by interfering with tubular secretion in the proximal tubule and also 1 protein binding of methotrexate (a relatively minor effect). Probenecid competes with methotrexate for renal elimination Avoid co-administration if possible if not possible, 1 dose of methotrexate and monitor FBC closely... 

Bolin, J. T., Filman, D. J., Matthews, D A., Hamlin, R. C., and Kraut, J. Crystal structures of Eschenchia coh and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. J, Biol. Chem. 257, 13650-13662 (1982). 

Singh UC, Benkovic SJ. A free energy perturbation study of the binding of methotrexate to dihydrofolate reductase. Proc Natl Acad Sci U S A 1988 85 9519-9523. 

Bolin J T, D J Filman, D A Matthews, R C Hamlin and J Kraut 1982. Crystal Structures of Escherichia coli and Lactobacillus casei Dihydrofolate Reductase Refined at 1.7 Angstroms Resolution. I. Features and Binding of Methotrexate Journal of Biological Chemistry 257.13650-13662. 

U. C. Singh and S. J. Benkovic, Proc. Natl. Acad. Sci. U.S.A., 85, 9519 (1988). A Free Energy Perturbation Study of the Binding of Methotrexate to Mutants of Dihydrofolate Reductase. 

Parish RC, Johnson V. Effect of salicylate on plasma protein binding of methotrexate. Clin Pharmacol Ther( 996) 59,162. 

Probenecid inhibits the renal excretion of methotrexate in both monkeys and rat and this probably also happens in man. Changes in the protein binding of methotrexate may also have some part to play. The increased methotrexate levels increase the risk of serious bone marrow depression. 

I xton JW. Interaction of jrobenecid with the protein binding of methotrexate Pharmacology (1984) 28, 86-9. 

The different locations and bindings of methotrexate and the diamino-pyrim-idine and -triazine inhibitors, in these analogous enzymes, will be described in Section 9.3.3, with stereo-drawings. 

For a review of n.m.r. studies of the binding of methotrexate 9.29) and of 2,4-diaminopyrimidine, both of them inhibitors, to the dihydrofolate reductase of L. casei, see Roberts etal. (1977). 

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