Molecular dynamics simulations of the HIV-1 integrase dimerization interface: guidelines for the design of a novel class of integrase inhibitors.

HIV-1 integrase (IN) is a validated target of anti-AIDS research. The classical approach of designing active-site directed ligands has largely been exploited. A promising alternative strategy to inactivate the enzyme is to prevent the formation of IN dimers. The rational design of dimerization inhibitors, however, is hampered by the lack of relevant structural data about the targeted monomeric form. Therefore, we performed molecular dynamics simulations and subsequent analyses to gain insight into the structural features of the IN catalytic-core-domain dimerization interface. As a result, the formation of a groove and a cavity along the dimerization interface of the IN monomer could be revealed. Both were shown to be suited for accommodating an inhibitory peptide. The results form a valuable basis for the design of ligands targeting the dimerization interface and, thus, of a whole new class of HIV-1 integrase inhibitors.