Structural studies on antifolate drugs.

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Aston University. Department of Pharmaceutical Sciences , Birmingham
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Citation Information. Carl H. Schwalbe, Vivian Cody (). Structural Studies of Antifolate Drugs. In St. Andrews, Scotland. Antifolate drugs, such as the dihydrofolate reductase (DHFR) inhibitor methotrexate (MTX), have been used in the treatment of cancer for more than 50 years.

Increased understanding of the biochemistry of folate-dependent pathways, folate transporters, drug resistance, and downstream effects of Structural studies on antifolate drugs. book inhibition has led to the discovery of new generations of antifolate drugs.

These structural differences from folic acid confer on these analogs an extremely high affinity for DHFR. The primary action of aminopterin and methotrexate (MTX), the “classical” antifolates, is the inhibition of this enzyme.

The 4-amino antifolates are among the most potent enzyme inhibitors known. The antifolates remain a topic of continuing fascination to pharmacologists.

This in-terest is not entirely theoretical. Recent years have seen two new antifolate drugs approved for marketing: trimetrexate (Neutrexin), a lipophilic inhibitor of dihydrofolate reductase (DHFR) for treatment of the life-threatening fungal infection, Pneumocystis carinii pneumonia; and the thymidylate synthase (TS) inhibitor, raltitrexed (Tomudex), for colorectal cancer.

Antifolate drugs are used as antimalarials through their inhibition of folate metabolism of the parasite, both in the synthesis and use of folate cofactors. Humans do not make any folate cofactors, relying only on exogenous supply, and are therefore mostly spared from the effects of antifolate drugs.

The key enzyme targets are dihydropteroate synthase (DHPS), inhibited by sulfa drugs, and. Antifolate drugs are molecules directed to interfere with the folate metabolic pathway at some level.

They can be recognized among the first rationally designed compounds applying the principle of structural analogy with the substrate developing the antimetabolite strategy. Chemical structures of methotrexate and other diaminopteridine derivatives.

The binding mode of methotrexate is highly conserved in PTR enzymes as demonstrated by the structural characterization of the complexes with Lm PTR1 (PDB id 1E7W), 9 Tc PTR2 (PDB id 1MXF), 13 and Tb PTR1 (PDB id 2C7V) 12 (Fig. In Antifolate Drugs in Cancer Therapy, Ann Jackman and a panel of highly regarded researchers comprehensively review the current status of novel antifolates, an important class of anticancer drugs.

The distinguished contributors discuss the preclinical and clinical pharmacology of methotrexate, other dihydrofolate reductase inhibitors. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance.

This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate by: Novel antifolate drugs.

due to the structural similarity of MTX with FA and presence of FA receptor as targeting ligand on the surface of the was attributed to study drug in one patient. Europe PMC is an Elixir Core Data Resource Learn more ›.

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Europe PMC is a service of the Europe PMC Funders' Group, in partnership with the European Bioinformatics Institute; and in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine (NCBI/NLM).It includes content provided to the PMC International archive by participating : Patrick K.

Bryant. In Antifolate Drugs in Cancer Therapy, Ann Jackman and a panel of highly regarded researchers comprehensively review the current status of novel antifolates, an important class of anticancer drugs.

The distinguished contributors discuss the preclinical and clinical pharmacology of methotrexate. In Antifolate Drugs in Cancer Therapy, Ann Jackman and a panel of highly regarded researchers comprehensively review the current status of novel antifolates, an important class of anticancer drugs.

Description Structural studies on antifolate drugs. PDF

Structural studies on antifolate drugs Author: supporting and enhancing data obtained in the lower resolution studies of protein crystallography. The biological importance of these compounds is discussed and an attempt is made to relate/predict their pharmacological activity to observed structural features in the crystalline environment Author: Patrick K.

Bryant. In Antifolate Drugs in Cancer Therapy, Ann Jackman and a panel of highly regarded researchers comprehensively review the current status of novel antifolates, an important class of anticancer drugs.

The distinguished contributors discuss the preclinical and clinical pharmacology of methotrexate, other dihydrofolate reductase inhibitors, Format: Hardcover. The anticancer activity of antifolates can be enhanced if they are given with drugs that inhibit nucleoside transport by preventing neoplastic cells from recovering nucleoside precursors.

Currently, it serves as the principle biochemical prototype for the clinical research of all new antifolates. Structural Studies on Bioactive Compounds.

Part Design, Synthesis and Biological Evaluation of Pyrimethamine-Based Antifolates Against Pneumocystis carinii. Bioorganic & Medicinal Chemistry10 (9), DOI: /S(02) Cited by: 3. Structure-based design of non analog antifolate inhibitors. Thymidylate synthase remains a good target for structure-based drug design.

Over 90 X-ray crystal structures have been solved sincewhen the first X-ray structure of the apoenzyme from Lactobacillus casei was determined in Stroud's laboratory at UCSF in San by: Abstract. Besides its important role in folate homeostasis, membrane transport is a critical determinant of the antitumor activities of antifolate therapeutics used in cancer chemotherapy, such as methotrexate (MTX) and an exciting new generation of antifolates typified by Tomudex and r, impaired cellular uptake of antifolates is a frequent mode of drug by: 1.

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Structural Studies on Bioactive Compounds. Part Design, Synthesis and Biological Evaluation of Pyrimethamine-Based Antifolates Against Pneumocystis carinii. Bioorganic & Medicinal Chemistry10 (9), DOI: /S(02)Cited by:   Antifolate drug metabolism. As structural analogs of folates, antifolates use the same transport systems to enter the cells, namely the reduced folate receptor (RFC), folate receptors (FR), and the recently discovered proton-coupled folate transporter (PCFT) or soluble carrier 46A1 (SLC46A1).

16 The RFC plays a dominant role in cellular uptake of antifolates, as it has low affinity to its main Cited by: Title:In Silico Structure Modeling and Molecular Docking Analysis of Phosphoribosyl Pyrophosphate Amidotransferase (PPAT) with Antifolate Inhibitors VOLUME: 19 ISSUE: 5 Author(s):Nousheen Bibi*, Zahida Parveen, Muhammad Sulaman Nawaz and Mohammad Amjad Kamal Affiliation:Department of Bioinformatics, Shaheed Benazir Bhutto Women University Peshawar, Peshawar, KPK, Department Author: Nousheen Bibi, Zahida Parveen, Muhammad Sulaman Nawaz, Mohammad Amjad Kamal.

New patent disclosures reveal novel antifolate scaffolds, antifolates with improved drug-like properties and new strategies to effectively target cancer cells. The continued use of high resolution structural information has guided the discovery of several by: The x-ray structure of the Pneumocystis carinii dihydrofolate reductase (DHFR):trimethoprim:NADPH ternary complex obtained from the Protein Databank was used as a structural template to generate models for the following complexes: P.

carinii DHFR:piritrexim:NADPH, P. carinii DHFR:epiroprim:NADPH, and P. carinii DHFR:trimetrexate:NADPH. Each of these complexes, Cited by: 3. Start studying Antifolate drugs. Learn vocabulary, terms, and more with flashcards, games, and other study tools.

Introduction. Antifolates, such as methotrexate, were one of the earliest classes of drugs developed for clinical use in cancer chemotherapy. Today, methotrexate is still used extensively in the treatment of human leukemia, breast cancer, head and neck cancer, choriocarcinoma, osteosarcoma, and by:   The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes.

Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed.

In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to Cited by: 9. 3D-QSAR Studies on the Inhibitory Activity of Trimethoprim Analogues against Escherichia coli Dihydrofolate Reductase.

Chemical Biology & Drug Design79 (6), DOI: / by:   As observed in previous clinical studies with pemetrexed and other antifolate drugs, transient grade 3 and 4 elevations of transaminases were observed but were not dose-limiting. The addition of folic acid and vitamin B 12 decreases the frequency of severe clinical toxicities of pemetrexed and allows this agent to be applied clinically with a Cited by: Antifolates are an important class of anticancer drugs originally developed as anti leu- kemic agents, but now used, usually in combination with other drugs, for the treatment of a wide range of tumors, notably carcinomas of the head and neck, breast, germ cell tumors, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and osteogenic sar- comas.

5-Fluorouracil and its prodrugs also target Missing: Structural studies. Surprisingly, few experimental studies have focused on the dynamical consequences of drug inhibition.

Herein, we detail a structural and multi-timescale dynamical study of Escherichia coli dihydrofolate reductase bound to its cofactor NADPH and to either of the small molecule drugs methotrexate (MTX) or trimethoprim (TMP).Cited by:   NMR is one of the most powerful methods for imaging of biomolecules.

This book is the ultimate NMR guide for researchers in the biomedical community and gives not only background and practical tips but also a forward looking view on the future of NMR in systems biology.

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors rational drugs design was in silico docking study Cited by: 1.