Modeling flexible pharmacophores with distance geometry, scoring, and bound stretching.

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    The study of pharmacophores, i.e., of common features between different ligands, is important for the quantitative identification of "compatible" enzymes and binding species. A pharmacophore-based technique is developed that combines multiple conformations with a distance geometry method to create flexible pharmacophore representations. It uses a set of low-energy conformations combined with a new process we call bound stretching to create sets of distance bounds, which contain all or most of the low-energy conformations. The bounds can be obtained using the exact distances between pairs of atoms from the different low-energy conformations. To avoid missing conformations, we can take advantage of the triangle distance inequality between sets of three points to logically expand a set of upper and lower distance bounds (bound stretching). The flexible pharmacophore can be found using a 3-D maximal common subgraph method, which uses the overlap of distance bounds to determine the overlapping structure. A scoring routine is implemented to select the substructures with the largest overlap because there will typically be many overlaps with the maximum number of overlapping bounds. A case study is presented in which 3-D flexible pharmacophores are generated and used to eliminate potential binding species identified by a 2-D pharmacophore method. A second case study creates flexible pharmacophores from a set of thrombin ligands. These are used to compare the new method with existing pharmacophore identification software. © 2012 American Chemical Society.
    Original languageEnglish
    Pages (from-to)577-588
    Number of pages11
    JournalJournal of Chemical Information and Modeling
    Issue number2
    Publication statusPublished - 27 Feb 2012

    Research Beacons, Institutes and Platforms

    • Manchester Institute of Biotechnology


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