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

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 the classical folate TS inhibitors. This indicates a potential allosteric binding site useful for future drug discovery studies. © 1998 John Wiley & Sons, Inc. Med Res Rev, 18, No. 1, 21‐42, 1998.