Publications on dihydrofolate reductase dhfr inhibitors. In cellular functions, dihydrofolate reductase dhfr is an enzyme that reduces 7,8dihydrofolate dhf to 5,6,7,8tetrahydrofolate thf using nadph as electron donor. Selective inhibitors of dihydrofolate reductase figure 11. Dihydrofolate reductase inhibitors as potential drugs. Sulphonamides, sulphones, and dihydrofolate reductase inhibitors. We investigated impairment of we use cookies to enhance your experience on our website. Dihydrofolate reductase is a small enzyme that plays a supporting role, but an essential role, in the building of dna and other processes. Inhibitors of dihydrofolate reductase have antibiotic, antimalarial and antineoplastic properties. The results show that the bound human thymidylate synthase and dihydrofolate reductase are capable of substrate channeling and the formation of the surface electrostatic highway. Dihydrofolate reductase dhfr has been used as a target for antimicrobial drug discovery against a variety of pathogenic microorganisms, including opportunistic microorganisms. Molecular modeling study of dihydrofolate reductase.
Evaluation of potent inhibitors of dihydrofolate reductase in a culture. Insight into inhibitory activity of mycobacterial dihydrofolate reductase inhibitors by insilico molecular modeling approaches. A dihydrofolate reductase inhibitor dhfr inhibitor is a molecule that inhibits the function of. Rational design of novel allosteric dihydrofolate reductase. Ic50 for the enzyme for inhibition of paminobenzoic acid.
Sulphonamides, sulphones, and dihydrofolate reductase inhibitors the sulphonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most grampositive and many gramnegative organisms. Examples of recent studies in the development of new dhfr inhibitors i. Isolation of chinesehamster cell mutants deficient in. Competitive inhibition of folate absorption by dihydrofolate. Vectors containing the wild type gene, whose coding. Although structurally belonging to different classes, the majority of dhfr inhibitors contain 2, 4diamino substitution in pyrimidine ring. By continuing to use our website, you are agreeing to our use of cookies. Approaches to soft drug analogues of dihydrofolate reductase. Inhibitors of multiple mutants of plasmodium falciparum. Discovery of selective toxoplasma gondii dihydrofolate. This antimicrobial drug class includes sulfonamides, dihydrofolate reductase inhibitors and combinations of these two subclasses. Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. Dihydrofolate reductase dhfr, a key enzyme in thymidine synthesis, catalyzes the nadph dependent reduction of dihydrofolate dhf to tetrahydrofolate thf and.
In this regard, several dhfr inhibitors are reported against pc and tg and ma. 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. Inhibitors of dihydrofolate reductase dhfr, an enzyme that catalyzes 5, 6, 7, 8tetrahydrofolate synthesis, have been used as antimicrobial as well as antimetabolite drugs for a long time. Sulphonamides, sulphones, and dihydrofolate reductase.
It manages the state of folate, a snaky organic molecule that shuttles carbon atoms to enzymes that need them in their reactions. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase dhfr, a key enzyme in the synthesis of thymidylate, and. 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. Study reveals shapeshifting enzyme dihydrofolate reductase. It catalyzes tetrahydrofolate regeneration by reduction of dihydrofolate, using nadph as a cofactor. Dihydrofolate reductase dhfr is a member of the reductase family of enzymes that is ubiquitously expressed in all organisms. Novel 2,4 diaminopyrimidine derivatives or substituted 2,4 diaminopyrimidines and other compounds. 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. Hybrid inhibitors of malarial dihydrofolate reductase with. Comprehensive summaries of uppsala dissertations from the faculty of pharmacy 252. A dihydrofolate reductase inhibitor dhfr inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate. Clinical pharmacology and resistance to dihydrofolate. Sulphonamides, sulphones, and dihydrofolate reductase inhibitors the sulphonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most grampositive and. A molecular modeling study on dihydrofolate reductase dhfr inhibitors was carried out.
Dihydrofolate reductase dhfr inhibitors pharmacorama. 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. Sulfa and trimethoprimlike drugs antimetabolites acting as. Pdf dihydrofolate reductase dhfr was discovered in the late 1950s by investigators. Tapale aissms college of pharmacy, kennedy road, near rto office, pune 411 041. Novel 2,4diaminopyrimidine derivatives or substituted 2,4 diaminopyrimidines and other compounds. The significance of the latter enzyme and the clinical use of several of its inhibitors has been discussed 6 91. Later that year, osborn and huennekens recognized that dhf was the preferable substrate for the enzyme, so they dubbed the enzyme, dihydrofolate reductase, the name we use today. 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. Dihydrofolate reductase dhfr is the enzyme responsible for the nadphdependent reduction of 5,6dihydrofolate to 5,6,7,8tetrahydrofolate, an essential cofactor in the synthesis of purines.
Major indications for the use of folate inhibitor combinations are urinary tract infections, enteric infections caused by susceptible strains of gramnegative bacteria, specific respiratory infections and toxoplasmosis. Pdf synthesis and biological evaluation of a new series of. Dhfr while mtx, an antifolate compound, inhibits both. The crystal structures of two human dihydrofolate reductase hdhfr ternary complexes, each with bound nadph cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. Keywords antibacterial, carbonic anhydrase, dihydrofolate reductase, dihydropteroate synthase, sulfa drug, trimethoprim history received 21 february 20 revised 15 march 20. With the aim to introduce pyrimidopyrimidines as a novel class. Inhibitors of dhfr must have a sufficient specificity for the dhfr of microorganisms and that of cancerous cells for not inducing too many adverse effects in humans. Its therapeutic utility depends mainly on differences in uptake, glutamylation, cellular excretion, cellular metabolic balance, and other factors. Dihydrofolate reductase dhfr, tetrahydrofolate dehydrogenase. Dihydropteroate synthase sulfonamides and dihydrofolate. Expression of the plasmidencoded type i dihydrofolate. This study focuses on structure of dihydrofolate, its interaction with specific amino acids, mechanism of dhfr catalysis. Dihydrofolate reductase inhibitors have also been used to combat malaria. Dihydrofolate reductase from a methotrexateresistant mutant strain a of strepto coccus faecium var.
Trimethoprim and pyrimethamine, inhibitors of dihydrofolate reductase dhfr, cause folate deficiency in some patients. Dihydrofolate reductase inhibitors as potential drugs wiley online. Tapale aissms college of pharmacy, kennedy road, near rto office, pune 411 041, maharashtra, india. Dec, 2018 the s108n mutation of dihydrofolate reductase dhfr renders plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Dihydrofolate reductase from bacillus anthracis badhfr a validated drug target in the treatment of the infectious disease, anthrax. Rodrigues, sam tonddastnavaei, eugene shakhnovich, and je. It inhibits dihydrofolate reductase dhfr, the enzyme contributing to the production of tetrahydrofolate and its byproducts which are necessary for thymidylate and. 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 anti. Methotrexate inhibits dhfr with a high affinity, thus reducing the. Pdf synthesis and biological evaluation of a new series. Dihydrofolate reductase dhfr, a key enzyme in thymidine synthesis, catalyzes the nadph dependent reduction of dihydrofolate dhf to tetrahydrofolate thf and, at much lower rate, the conversion of folate to thf. Pneumocystis carinii pc, toxoplasma gondii tg and mycobacterium avium complex ma.
Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. Rational design of novel allosteric dihydrofolate reductase inhibitors showing antibacterial e. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase dhfr. Mtxresistant clones isolated fromseveral different rodent cell lines usually exhibit one of the following three.
Dihydrofolate reductase assay kit cs0340 technical bulletin. Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced. Substrate channeling between the human dihydrofolate. Badhfr is less sensitive to trimethoprim analogs than is dihydrofolate reductase from other species such as escherichia coli, staphylococcus aureus, and streptococcus pneumoniae. Dihydrofolate reductase inhibitors as potential drugs, chemischer informationsdienst, 1982, 2wiley online library pdf info. Inactivation of bacterial dihydrofolate reductase concomitant with modification of a methionine residue at the active site received for publication, september 14, 1973, and in revised form, august 20, 1974 john m. Synthesis and biological evaluation of a new series of dihydrofolate reductase inhibitors based on the 42,6diamino5pyrimidinylalkyllglutamic acid structure. 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. Researchers from the university of groningen have visualized the characteristics of a single enzyme within a nanopore. The fact that so few antibacterial dhfr inhibitors have reached the public does not mean that the chemist and biologist have been idle in this area for the past. The manifestations of methotrexate toxicity depend of the route of administration, dose, and the use of other treatment modalities such as irradiation.
Selective inhibitors of bacterial dihydrofolate reductase. Methotrexate is a dihydrofolate reductase inhibitor used in the treatment of leukemia, lymphomas including central nervous system lymphoma, choriocarcinoma, breast cancer, osteosarcoma, and leptomeningeal metastases. Mar 25, 1988 a recombinant plasmid has been designed to express the gene encoding a type i methotrexateresistant dihydrofolate reductase, derived from the bacterial plasmid r483, in dhfr chinese hamster ovary cells. Dhfr has a key role in cell growth and proliferation. Pdf insight into inhibitory activity of mycobacterial. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.
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. Approaches to soft drug analogues of dihydrofolate reductase inhibitors. Folate inhibitors antagonize the synthesis of folic acid and are used for treating bacterial, fungal and protozoal infections. Study reveals shapeshifting enzyme dihydrofolate reductase is associated with catalysis. Pdf dihydrofolate reductase as a therapeutic target researchgate. By combining molecular dynamics simulations with semiempirical pm6, ab initio, and density functional theory dft calculations, a simple and generally applicable procedure to evaluate the binding energies of dhfr inhibitors interacting with the human enzyme is reported here, providing a clear picture of. The manifestations of methotrexate toxicity depend of the route of administration, dose, and the use of other treatment. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.