Novel HIV integrase inhibitors with anti-HIV activity: insights into integrase inhibition from docking studies

The mechanism of integrase is generally accepted to be dependant on the presence of two divalent metal ions in the active site. However, the only available crystal structures of HIV-1 integrase contain either one or no metal ions, hampering structure-based design studies of integrase inhibitors. For this reason, a two-metal ion model of integrase was constructed. This model was used for computational docking studies with novel diketoacid integrase inhibitors containing pyrimidine nucleobase scaffolds. The docking protocol allowed for some steric contact between the ligand and protein during docking simulations, which implicitly accounted for potential conformational changes in the protein as a result of binding viral DNA or the ligand. The results suggest that the aromatic rings in these diketo acids bind to regions close to the viral DNA and may interfere with mobility of a vital catalytic loop. The docking data also suggest that the ligand can be prevented from adopting a favourable conformation by changes in the relative orientation of its diketo side-chain and aromatic rings. The docked pose of each of the active compounds coordinated both of the metal ions present in the active site of integrase through the diketo acid functionality of these compounds. This result is more consistent with theoretical data on inhibitor mechanism, and thus recommends this docking approach over rigid use of one-metal ion models derived from current crystal structures of integrase.