This component provides a mechanism for establishing an extensive library of detailed x-ray diffraction and thermodynamic data on a large variety of structurally distinct inhibitors bound to HIV protease and E. coli thymidylate synthase. This information will be used by other components of this program project to develop, parameterize and evaluate an intelligent systems approach to de novo design of lead compounds, a knowledge based method for correlating three dimensional structure and binding constants, and a semi-empirical approach for calculating protein: ligand binding free energies. Within this database will also reside atomic coordinates for proteins whose three dimensional x-ray structures will be utilized in the eventual application of the above methods for prospective design of new therapeutic agents for treatment of AIDS. These include structures for HIV protease, Rnase H, and integrase and for protozoal bifunctional dihydrofolate reductase/thymidylate synthase, a target for control of AIDS associated opportunistic infections.
