Thymidylate synthase inhibition: A structure-based rationale for drug design

Costi, Maria Paola

doi:10.1002/(sici)1098-1128(199801)18:1<21::aid-med2>3.0.co;2-u

Cited by 21 publications

(17 citation statements)

References 94 publications

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“…Agents such as fluorouracil, and the newer antifolate drug Tomudex, have proved to be effective inhibitors of thymidylate synthase and are clinically established drugs in the treatment of cancer. Drugs targeting these enzymes have also been used as antibacterial and antiprotozoal agents by exploiting the differences between the catalytic sites of isoenzymes from the host and target organism [15][16][17]. With such considerable effort put into designing drugs against these enzymes, it is surprising that so little attention has been paid to the inhibition of SHMT.…”

Section: Introductionmentioning

confidence: 99%

The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy

1998

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The crystal structure shows the evolutionary relationship between SHMT and other alpha class PLP-dependent enzymes, as the fold is highly conserved. Many of the results of site-directed mutagenesis studies can easily be rationalised or re-interpreted in light of the structure presented here. For example, His 151 is not the catalytic base, contrary to the findings of others. A mechanism for the cleavage of serine to glycine and formaldehyde is proposed.

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Section: Introductionmentioning

confidence: 99%

The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy

1998

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“…The bio‐profiling studies suggested that the halogen‐substituted phthaleins exhibit potential as cancer chemotherapeutics. Phenolphthalein 1 , tetrabromophenolphthalein 6 , tetrachlorophenolphthalein 7 and tetraiodophenolphthalein 8 have been reported as TS inhibitors .…”

Section: Biological Applications Of Phthalein Dyesmentioning

confidence: 99%

Developments in the chemistry and applications of phthalein dyes. Part 2: biological applications

Sabnis¹

2018

Coloration Technology

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This review describes the huge impact of phthalein dyes on multiple industries. Although phthalein dyes demonstrate several vital applications, there appears to be no review in the literature. Part 2 of the review focuses on developments in the chemistry and biological applications of phthalein dyes. The biological applications of phthalein dyes are grouped into agrochemical, biochemical, food, personal care, pharmaceutical and sensors applications. The importance of these dyes in various commercial products is also revealed, and patent analysis is provided in the Appendix. The uses of phthalein dyes in various fields are important but their growing popularity with fascinating colour change features is particularly notable. Part 1 of the review focused on developments in the chemistry and industrial applications of phthalein dyes. The industrial applications of phthalein dyes are grouped into building/construction applications, coatings applications, electronic/electrical applications and miscellaneous applications.

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“…The methylene group and the hydride are transferred from different sites of the folate to the substrate 2’-deoxyuridine-5’-monophosphate (dUMP), thus forming dTMP (Scheme 2). TSase is overexpressed in cancerous cells to facilitate faster cell growth, [59] which makes TSase a target for chemotherapeutic drugs, but common drugs such as antifolates and 5-fluorouracil often interfere with the metabolic processes of healthy cells, resulting in toxicity [60]. Careful investigation of the TSase mechanism may lead to the discovery of drugs that selectively target malignant tumor cells.…”

Section: Folate In Thymidylate Synthasementioning

confidence: 99%

Kinetic isotope effects as a probe of hydrogen transfers to and from common enzymatic cofactors

Roston

Islam

Kohen

2014

Archives of Biochemistry and Biophysics

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Enzymes use a number of common cofactors as sources of hydrogen to drive biological processes, but the physics of the hydrogen transfers to and from these cofactors is not fully understood. Researchers study the mechanistically important contributions from quantum tunneling and enzyme dynamics and connect those processes to the catalytic power of enzymes that use these cofactors. Here we describe some progress that has been made in studying these reactions, particularly through the use of kinetic isotope effects (KIEs). We first discuss the general theoretical framework necessary to interpret experimental KIEs, and then describe practical uses for KIEs in the context of two case studies. The first example is alcohol dehydrogenase, which uses a nicotinamide cofactor to catalyze a hydride transfer, and the second example is thymidylate synthase, which uses a folate cofactor to catalyze both a hydride and a proton transfer.

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Thymidylate synthase inhibition: A structure-based rationale for drug design

Cited by 21 publications

References 94 publications

The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy

The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy

Developments in the chemistry and applications of phthalein dyes. Part 2: biological applications

Kinetic isotope effects as a probe of hydrogen transfers to and from common enzymatic cofactors

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