Computational and synthetic approaches for the discovery of HIV-1 integrase inhibitors

In recent years our research group has been engaged in the structure-function study of IN enzyme and in the development of new HIV-1 IN-inhibitors. We first developed three-dimensional hypothetical pharmacophore models for the binding of IN inhibitors to the enzyme. In particular we focused our attention on. β-diketo acid (DKA) derivatives which represent the major leads in the development of anti-HIV-1 IN drugs, considering that the only two IN inhibitors undergoing clinical trials belong to this family. The resulting pharmacophore models allowed the discovery of new potential IN inhibitors, both through rational design and virtual screening. Biological testing showed that our strategy was successful in searching for new structural leads as HIV-1 IN inhibitors. In addition we built a plausible model of the full-length HIV-1 integrase dimer complexed with viral DNA on which molecular dynamics simulation studies were carried out.