Atomic resolution structures are to be determined by x-ray crystallography for 10 therapeutically important targets. One is for human thymidylate synthase, the rate-limiting enzyme that provides the sole de novo pathway for synthesis of the DNA-base dTMP from the RNA base dUMP. Human thymidylate synthase (TS) is a recognized target for anti- cancer therapeutics. Atomic structures will facilitate the proposed development of highly selective, high affinity inhibitors that seek to avoid other deleterious side effects. Improvements in current inhibitors, and de novo approaches to discovery of new compounds based upon the structure of each target protein will be used to facilitate drug development. The structures of TSs from 9 pathogenic organisms are to be determined as the basis of antiproliferative drug development using structure: five, TSs from Pneumocystis carinii. Mycobacterium tuberculosis, (avian and leprae), Cryptococcus neoformans and Toxoplasma gondii are the source of the major opportunistic infections which cause early death in patients with AIDS; four are from protozoa that are responsible for major worldwide disease: Plasmodium falciparum, malaria; Trypanosoma cruzi. Trypanosoma brucei (Chagas' disease); and Leishmania major (Leishmaniasis). From the structures of these species of enzyme, compounds with selectivity for the infective agent versus human will be developed by structure-based methodologies. New drug leads are to be developed along proposed lines, and using iterative cycles of structure-based development, followed by assays for affinity and selectivity, and structure analysis. Current computational approaches to estimation of the expected change in amity brought about by a suggested synthetic change in a drug or inhibitor molecule will be applied to assist in structure-based drug design. Public domain access to the structures of therapeutic targets and technology will encourage their use by major pharmaceutical companies for the better design of therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063081-05
Application #
2856363
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Lees, Robert G
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Keatinge-Clay, Adrian T; Shelat, Anang A; Savage, David F et al. (2003) Catalysis, specificity, and ACP docking site of Streptomyces coelicolor malonyl-CoA:ACP transacylase. Structure 11:147-54
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