Induced-fit docking approach provides insight into the binding mode and mechanism of action of HIV-1 integrase inhibitors.

A three-dimensional model of a complex between HIV-1 integrase (IN), viral DNA, and metal ions that we recently built was used as a target for a docking method (induced-fit docking, IFD) that accurately predicts ligand binding modes and concomitant structural changes in the receptor. Six different well-known integrase strand transfer inhibitors (INSTIs): L-708,906, L-731,988, S-1360, L-870,810, raltegravir, and elvitegravir were thus used as ligands for our docking simulations. The obtained IFD results are consistent with the mechanism of action proposed for this class of IN inhibitors, that is, metal chelating/binding agents. This study affords new insight into the possible mechanism of inhibition and binding conformations for INSTIs. The impact on our hypothesis of specific mutations associated with IN inhibitor resistance was also evaluated. All these findings might have implications for integrase-directed HIV-1 drug discovery efforts.