| Abstract
| - We present the first receptor-based pharmacophore model for HIV-1 integrase. The developmentof “dynamic” pharmacophore models is a new method that accounts for the inherent flexibilityof the active site and aims to reduce the entropic penalties associated with binding a ligand.Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystalstructure of the target protein. A molecular dynamics (MD) simulation describes the flexibilityof the uncomplexed protein. Many conformational models of the protein are saved from theMD simulations and used in a series of multi-unit search for interacting conformers (MUSIC)simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program;it is used to determine binding regions for probe molecules containing functional groups thatcomplement the active site. All protein conformations from the MD are overlaid, and conservedbinding regions for the probe molecules are identified. Those conserved binding regions definethe dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitorsof the integrase as well as a three-point, ligand-based pharmacophore model from the literature.Also, a “static” pharmacophore model was determined in the standard fashion, using a singlecrystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamicmodel but not the static model. Finally, we have identified a set of compounds from the AvailableChemicals Directory that fit the dynamic pharmacophore model, and experimental testing ofthe compounds has confirmed several new inhibitors.
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