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In summary, the quest for improved chemotherapeutic agents targeted against thymidylate synthase has provided not only important mechanistic insight along the way, but good inhibitors such as N10-propargyl-5,8-dideazafolate. These new folates, along with 5-fluorouracil, have provided objective responses in patients with some cancers. These efforts have spanned 30 years of research and have been empirically successful without the benefit if modern technologies, such as X-ray area detectors andcomputer modeling, and docking programs. These effort, define the basis for additional rationally design chemotherapeutic agents. To our knowledge, at least four groups are actively involved in solving the X-ray struc ture of bacterial and mammalian thymidylate synthases in the presence or absence of ligands. Once the three-dimensiorad structures of the native enzyme and its mutant forms wish ligands bound at the active site become available, a more integrated rational approach to the design of second. generation chemotherapeutic drugs specifically target towards thymidylate synthase will be possible.
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