While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductaselike genes have been identified on separate. Dihydrofolate reductase dhfr inhibitors pharmacorama. Inhibitors of dihydrofolate reductase in leishmania and. Screening of ligands against the mtb dhfr enzyme resulted in the identification of multiple fragment hits with ic 50 values in the range of 3890. Dihydrofolate reductase, dhfr, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Home pharmacology enzymes reductases dihydrofolate reductase dihydrofolate reductase inhibitors. Dhfr is crucial for proper cellular growth and proliferation, where it regulates the maintenance of tetrahydrofolate thf and its derivatives, leading to the synthesis of purine and thymidylates. Approaches to soft drug analogues of dihydrofolate. Kinetic and chemical mechanism of the dihydrofolate. Tapale aissms college of pharmacy, kennedy road, near rto office, pune 411 041, maharashtra, india. Tetrahydrofolate needs to be recycled so that reactions involved in dtmp synthesis and purine metabolism are maintained. Dhfr is a key folate metabolizing enzyme that catalyzes the reduction of folic acid into dihydrofolate.
Megaloblastic anemia due to dihydrofolate reductase deficiency. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. Dhfr inhibitors are usually 2,4diaminopyrimidines, which have high binding affinity to the enzyme but have the potential to inhibit the human enzyme. It catalyzes tetrahydrofolate regeneration by reduction of dihydrofolate, using nadph as a cofactor. Molecular docking study suggested that compounds bind to receptor similarly to the most active inhibitors. Chemical space of escherichia coli dihydrofolate reductase. Dihydrofolate reductase assay kit cs0340 technical. In silico study probes potential inhibitors of human. A dihydrofolate reductase inhibitor dhfr inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. Rational design of novel allosteric dihydrofolate reductase inhibitors showing antibacterial effects on drugresistant escherichia. Properties of an altered dihydrofolate reductase amplified genes. Function dhfr is a key enzyme in folate metabolism as it is involved in 5,10methylene tetra hydro folate thf generation from.
Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. While the dihydrofolate reductase enzyme is thought to be present in multiple cellular compartments, it is most particularly localized in the cytosol and the nucleoplasm. By use of the in vivo intestinalloop methods in rats, absorption of 3h folic acid was significantly decreased in the presence of either drug. Risk of heart defects in infants was increased with maternal treatment using dihydrofolate reductase dhfr inhibitors during pregnancy, but this risk was reduced for women who also took folic acid supplements. Methotrexate mtx, also an antifolate inhibitor of dihydrofolate reductase dhfr, soon after replaced aminopterin in the clinic and is used widely not only for the treatment of various forms of cancer, such. Click on the link to view a sample search on this topic. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Dihydrofolate reductase dhfr inhibitors are an important class of therapeutic compounds including antiparasitic agents. Dihydrofolate reductase dhfr inhibitors have been used successfully in the treatment of a number of other diseases such as cancer, malaria and bacterial.
Rosowsky a, mota ce, queener sf, waltham m, ercikanabali e, bertino jr. Dihydrofolate reductase dhfr is a member of the reductase family of enzymes that is ubiquitously expressed in all organisms. Study reveals shapeshifting enzyme dihydrofolate reductase. Escherichia coli dihydrofolate reductase is an important enzyme that is essential for the survival of the gram. We explored the activity of a series of novel dhfr inhibitors against s. The disclosure also provides pharmaceutical compositions thereof. Dihydrofolate reductase assay kit catalog number cs0340 storage temperature 20 c technical bulletin product description dihydrofolate reductase dhfr is a ubiquitous enzyme present in all eukaryotic and prokaryotic cells, playing a key role in thymidine synthesis. Major indications for the use of folate inhibitor combinations are urinary tract infections, enteric infections caused by susceptible. Dihydrofolate reductase dhfr was discovered in the late 1950s by investigators searching for folatedependent enzymes involved in 1carbon metabolism, with its already known application as anticancer and as antibiotics. We investigated impairment of intestinal folate absorption by these drugs. Dihydrofolate reductase inhibitors are an important class of drugs. Cryptosporidiosis is an emerging infectious disease that can be lifethreatening in an immunecompromised individual and causes gastrointestinal distress lasting up to 2 weeks in an immunecompetent individual. They are used in the treatment and prophylaxis of major infectious diseases, such as malaria, toxoplasmosis and pneumocystis carinii pneumonia. Hubbell jp, henning ml, grace me, nichol ca, sigel cw 1978 noxide metabolites of the 2,4diaminopyrimidine inhibitors of dihydrofolate reductase, trimethoprim, pyrimethamine and metoprine.
Clinical pharmacology and resistance to dihydrofolate. Dihydrofolate reductase is a small enzyme that plays a supporting role, but an essential role, in the building of dna and other processes. Specifically, dhfr catalyzes the reduction of folate and 7,8 dihydrofolate dhf to 5,6,7,8tetrahydrofolate thf. In humans, the dhfr enzyme is encoded by the dhfr gene.
Some of the drugs that inhibit this enzyme can, as in the case of methotrexate, be used as anticancer drugs. Pdf dihydrofolate reductase as a therapeutic target researchgate. Sulphonamides, sulphones, and dihydrofolate reductase. Methotrexate is the dhfr inhibitor used most often in a clinical setting as an anticancer drug. M versus mtb dhfr and minimum inhibitory concentration mic values in the range of 31. A dihydrofolate reductase inhibitor, mtx blocks cell division. It has been almost 50 years since aminopterin, the first drug capable of inducing complete remissions in children with acute lymphoblastic leukemia all, was first tested 1. Finally, we proposed three compounds 26, 27, and 28, which showed a high predicted dihydrofolate reductase inhibitory activity. Lipidsoluble inhibitors of dihydrofolate reductase. Dihydrofolate reductase inhibitor an overview sciencedirect topics. Dihydrofolate reductase inhibitors download pdf info publication number wo2001053276a1. Wo2001053276a1 pctgb200267 gb0100267w wo0153276a1 wo 2001053276 a1 wo2001053276 a1 wo 2001053276a1 gb 0100267 w gb0100267 w gb 0100267w wo 0153276 a1 wo0153276 a1 wo 0153276a1 authority wo. I or a pharmaceutically acceptable salt thereof, wherein r 5, r 6 and z are as described herein.
There are few therapeutics available for effectively treating this disease. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase like genes have been identified on separate chromosomes. Dihydrofolate reductase dhfr was discovered in the late 1950s by investigators searching for folatedependent enzymes involved in 1carbon. Pdf dihydrofolate reductase dhfr was discovered in the late 1950s by investigators searching for. Folate inhibitors antagonize the synthesis of folic acid and are used for treating bacterial, fungal and protozoal infections. Dihydrofolate reductase, dhfr, whose role is to regenerate folic acid into its reduced form tetrahydrofolate, is necessary for bacteria, plasmodia and normal and cancerous human cells. Using the nanopore system, maglia analyzed the enzyme dihydrofolate reductase dhfr, which transforms dihydrofolate into tetrahydrofolate. To measure the inhibition of dihydrofolate reductase activity by methotrexate or other folate analogs, either in the folate or dihydrofolate reduction. Efficacies of lipophilic inhibitors of dihydrofolate reductase against parasitic protozoa. Dihydrofolate reductase as a therapeutic target federation of.
Evaluation of potent inhibitors of dihydrofolate reductase in a culture. Structurebased approach to the development of potent and. It manages the state of folate, a snaky organic molecule that shuttles carbon atoms to enzymes that need them in their reactions. Inhibition of dihydrofolate reductase interferes with dna and protein synthesis. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists. Specifically, dhfr catalyzes the reduction of folate and 7,8dihydrofolate dhf to 5,6,7,8tetrahydrofolate thf. Dihydrofolate reductase is required for the development of. Dihydrofolate reductase dhfr, a key enzyme in thymidine synthesis, catalyzes the nadph dependent reduction of dihydrofolate dhf to tetrahydrofolate thf and. Some of them have little effect on the human enzyme but a strong effect on the dihydrofolate reductases of bacterial and other parasites. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase. Trimethoprim and other nonclassical antifolates an. Dihydrofolate reductase, or dhfr, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using nadph as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1carbon transfer chemistry. However, resistance to tmp, an inhibitor of dihydrofolate reductase enzyme dhfr, has challenged the efficacy of tmpsmx combination.
Mmv675968 from pathogen box inhibits acinetobacter baumannii. Dihydrofolate reductase dhfr is an important enzyme required to maintain bacterial growth, and hence inhibitors of dhfr have been proven as effective agents for treating bacterial infections. Antimicrobial dihydrofolate reductase inhibitors achievements and future options. Dhfr is known for its enzymatic action to catalyze the reduction of 7,8dihydrofolate dhf to 5,6,7. Methotrexate inhibits dhfr with a high affinity, thus reducing. Dihydrofolate reductase dhfr is a ubiquitous enzyme and exists in a wide range of organisms. Dihydrofolate reductase inhibitors tocris bioscience. Dhfr is known for its enzymatic action to catalyze the reduction of 7,8 dihydrofolate dhf to 5,6,7.
Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry. Pubmed is a searchable database of medical literature and lists journal articles that discuss megaloblastic anemia due to dihydrofolate reductase deficiency. Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. This antimicrobial drug class includes sulfonamides, dihydrofolate reductase inhibitors and combinations of these two subclasses. In addition, inhibitors of this enzyme, such as methotrexate, are used as anticancer drugs. Fragment discovery for the design of nitrogen heterocycles. Trimethoprimsulfamethoxazole tmpsmx combination has been used for treatment of s.
For example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing. Function dhfr is a key enzyme in folate metabolism as it is involved in 5,10methylene tetra hydro folate thf generation from 7,8 dihydrofolate dhf. This study focuses on structure of dihydrofolate, its interaction with specific amino acids, mechanism of dhfr catalysis. Trimethoprim and pyrimethamine, inhibitors of dihydrofolate reductase dhfr, cause folate deficiency in some patients. Development of selective inhibitors of dihydrofolate. Tapale aissms college of pharmacy, kennedy road, near rto office, pune 411 041, maharashtra, india keywords. The present disclosure provides compounds of formula i. With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics, and metabolism of a series of lipidsoluble 2,4diamino5phenylpyrimidine folate antagonists have been studied. Inhibitors of dihydrofolate reductase have antibiotic, antimalarial and antineoplastic properties. It catalyzes the reduction of 7,8dihydrofolate dhf to 5,6,7,8tetra. Inhibitors designed against this enzyme have demonstrated application as antibiotics.
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