PMID: 9436180Jan 22, 1998Paper

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

Medicinal Research Reviews
M P Costi

Abstract

Thymidylate synthase (TS) is a very interesting target in antiproliferative diseases. Its inhibition causes thimineless death of the cells and compounds inhibiting TS are widely used in anticancer therapy. The classical antifolate TS inhibitors are structural analogs of the folate cofactor; they often share the same metabolic pathways and this causes the development of resistance inside the cells. A detailed analysis of the available x-ray crystal structures of the complexes of the enzyme with different substrates and inhibitors support the finding of a structural basis of their biological activity. TS inhibitors nonstructural analog of folate, non-analog antifolate inhibitors (NAAI), are welcome as a new interesting research topic. Among the most recent and interesting ones, compounds from Agouron related to the indole structure, are independent on the folate metabolism, highly active and specific for human TS. Other compounds, phthalein derivatives, can inhibit TS enzymes from various sources and show an interesting biological activity profile: they inhibit better bacterial and fungal TS than human TS. The x-ray crystal structures of some of these inhibitors with TS show that they bind in a different binding site from that of...Continue Reading

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Citations

Oct 29, 2013·Archives of Biochemistry and Biophysics·Daniel RostonAmnon Kohen
Apr 25, 2013·Journal of the American Chemical Society·Zhen WangAmnon Kohen
Jun 27, 2002·Biochimica Et Biophysica Acta·M Paola CostiRobert M Stroud
Mar 18, 2008·Chembiochem : a European Journal of Chemical Biology·Sanuele CalòMaria Paola Costi

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