Developing a dynamic pharmacophore model for HIV-1 integrase

We present the first receptor-based pharmacophore model for HIV-1 integrase . The development of "dynamic" pharmacophore models is a new method that ac counts for the inherent flexibility of the active site and aims to reduce t he entropic penalties associated with binding a ligand. Furthermore, this n ew drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation descr ibes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of m ulti-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is us ed to determine binding regions for probe molecules containing functional g roups that complement the active site. All protein conformations from the M D are overlaid, and conserved binding regions for the probe molecules are i dentified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the inte grase as well as a three-point, ligand-based pharmacophore model from the l iterature. Also, a "static" pharmacophore model was determined in the stand ard fashion, using a single crystal structure. Inhibitors thought to bind i n the active site of HIV-1 integrase fit the dynamic model but not the stat ic model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experime ntal testing of the compounds has confirmed several new inhibitors.