The principal objective of this project has been to elucidate the structure of the HIV-1 integrase protein, complexed with DNA and/or inhibitors, to use the structural knowledge thus obtained to design better inhibitors of this enzyme with the goal of developing new anti-HIV drugs, and to apply any other computer-aided drug design method that may be helpful in identifying new, promising HIV-1 integrase inhibitors. HIV integrase (IN) is the virally encoded enzyme responsible for integration of the retroviral DNA into the host genome. This step in the life cycle of HIV is essential for viral replication. Inhibition of integration is seen as an attractive target in the development of anti-AIDS therapies because no cellular homologue to IN is known, thus raising the hope that effective anti-IN based drugs with low-toxicity can be developed. The emergence of multidrug-resistant virus phenotypes during administration of cocktails of protease and reverse transcriptase (RT) inhibitors further highlighted the need for alternative therapeutic approaches. The project "Exploration of Chemical-Biological Space via a Very Large Database of Synthesizable Compounds to Discover Novel Anti-HIV Agents" aimed at developing a workflow for efficient retrieval from the SAVI database (see Project 2) of compounds with complex predicted desirable ADMET characteristics to create a "SAVI-ADMET" subset; collection, analysis, curation, and usage of data (including protein expression, targets, and molecular mechanisms) for building of (Q)SAR models from publicly and commercially available databases about the main mechanisms of pathogenesis of HIV/AIDS and HIV-associated comorbidities (on the Russian side); identifying with these (Q)SAR models in SAVI-ADMET single- and multi-target ligands active against HIV-1 and against different types of HIV-related comorbidities; synthesis and biological testing of several tens of selected compounds either. After the source of the SAVI building blocks was changed to the building block set from Enamine, compounds were identified according to the criteria above and were ordered for synthesis and for subsequent assaying. While this project is winding down at the CADD Group, continued work in this project is done by our Russian collaborators.