Human enzymes inhibitors

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

A new tool for computational ADME/Tox called MetaDrug includes a manually annotated Oracle database of human drug metabolism information including xenobiotic reactions, enzyme substrates, and enzyme inhibitors with kinetic data. The MetaDrug database has been used to predict some of the major metabolic pathways and identify the involvement of P450s [78]. This database has enabled the generation of over 80 key metabolic... 

IC with bovine enzyme which is very similar to the human one. Inhibitor concentration for 50% inhibition. K of substrate (phenyl a-D-mannopyranoside). K of substrate (4-nitrophenyl a-D-manno-pyranoside). K of substrate (4-nitrophenyl D-glucosiduronic acid). K of substrate (4-nitrophenyl 2-acetamido-2-deoxy- o-glueoside). Inhibitors were chitotetraono-1,5-lactone and chitotetraose, respectively. 

The standard model for the preclinical development of anti-osteoporosis therapies is the ovariectomized (OVX) rat. However, Cat K inhibitors developed specifically against the human enzyme are generally significantly less potent ( 2-orders of magnitude) against the rat and mouse enzymes than against human Cat K [9]. This loss of potency towards the rodent enzymes, which is consistent with their low sequence homology, therefore restricts the use of... 

K. Yamanaka, S. Morikawa, K. Murata, K. Banno, T. Sato, T. Takai, T. Suzuki, M. Mi-zobe, M. Ito, K. Ishibashi, Radioimmunoassay for Imidapril, a New Angiotensin-Converting Enzyme Inhibitor, and Imidaprilat, Its Active Metabolite, in Human Plasma and Urine , J. Pharm. Biomed. Anal. 1996, 14, 281-287. 

Now we come to the question what is the basis of the antibacterial action of the sulfa drugs Many useful drugs in human medicine are enzyme inhibitors, small molecules that frequently bear a structural resemblance to the substrates or products of enzyme-catalyzed reactions. So it is with the sulfonamides. 

Lewis, D. F. V., Lake, B. G., Bird, M. G., Loizou, G. D., Dickins, M., and Goldfarb, P. S. (2003) Homology modelling of human CYP2E1 based on the CYP2C5 crystal structure Investigation of enzyme-substrate and enzyme-inhibitor interactions. Toxicol, in Vitro 17, 93-105. 

Examples of fluorine-containing imino sugars as partial structures of PNPs have been reported. The S -deoxy-S -fluoro compound 116 ( S -F-Imucillin H, Scheme 29) was found to be a nanomolar inhibitor of human PNP (1 nM) as well as that of Plasmodium falciparum (A) 60 nM).237 2,-Deoxy-2,2 -difluoro derivative 117 ( -diF-immucillin-H ) exhibited slightly more inhibitory power against the microbial enzyme and an enhanced selectivity of more than three orders of magnitude (ATj 1.4 nM vs. 15 pM).238 Another type of inhibitor, the 3-fluoro compound 118 ( F-DADMe-immucillin-H ) was shown a potent picomolar inhibitor of the human enzyme (Kf 32 pM), with some selectivity over the Plasmodium phos-phorylase (2.6 nM), whereas the enantiomer 119 was 50- to 100-fold less active 239,240... 

Trimethoprim is a competitive inhibitor of the enzyme dihydrofolate reductase and can thus prevent the formation of tetrahydrofolate thereby blocking the synthesis of purines. The affinity of trimethoprim for the enzyme in microorganisms is 10,000 times higher than for the human enzyme which explains the selective toxicity. Used alone its main indication is acute uncomplicated urinary tract infections. It is then as effective as co-trimoxazole but has the advantage of fewer adverse reactions. 

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