We describe the development and coordinated application of molecular biology, combinatorial chemistry and computational science for the development of anti HI-PR inhibitors specifically designed against drug resistant proteases. We demonstrate a unique microbial expression assay that identifies resistance conferring mutations with a striking correspondence to clinically relevant mutations. This assay for resistance has the advantages over mammalian cell culture of speed, reproducibility, exquisite sensitivity and inclusiveness. The expression assay system is also ideal for comparing inhibitors for efficacy against both native and variant proteases and for identifying single inhibitors or combinations for which resistance conferring substitutions occur infrequently. We propose to work in three areas: 1. Synthesis and testing of combinatorial libraries of potential protease inhibitors against native and variant proteases. 2. Computational science and computer modeling for creation of virtual chemical libraries, the modeling of protease variants and the identification of variant inhibitors. 3. Optimization of screening and positive selection techniques for the rapid identification of protease variants and their inhibitors. PROPOSED COMMERCIAL APPLICATION: Discovery of lead compounds for HIV protease therapeutic combinations against resistance. 2. Develop software for predicting changes in proteins that give rise to resistant variants.