A docking study of l-chicoric acid with HIV-1 integrase

Human immunodeficiency virus 1 integrase (HIV-1 IN) is the enzyme responsible for integrating the viral DNA into the host genome, and is essential to the replication of the virus. l-Chicoric acid (l-CA) is a bidentate catechol that has been identified as a potent inhibitor of HIV-1 IN. Using the new Autodock 4.0 free-energy function we have obtained a l-CA binding mode that explains its observed potency and is consistent with available experimental data. Because of the α,β-unsaturated ester functionality of the side arms of l-CA we first performed an extensive conformational analysis of l-CA using semiempirical and ab initio calculations. As a result we have identified two distinct l-CA binding modes, one for the s-cis/s-cis and another for the s-cis/s-trans isomers. The most stable conformer was found to be the structure with the α,β-unsaturated ester in the s-cis conformation for both arms of l-CA. This conformer also gave the top-ranked docking solution. Analysis of the interactions with key IN residues, combined with results using a l-CA tetraacetylated derivative and a Q148A IN mutant, correlate well with the experimental data.