title: Modeling flexible pharmacophores with distance geometry, scoring, and bound stretching.
abstract: 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.
authors.affiliation: School of Chemical Engineering and Analytical Science, University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Binns
authors.forename: Sam P
authors.initials: SP
authors.lastname: de Visser
authors.forename: Constantinos
authors.initials: C
authors.lastname: Theodoropoulos
mesh_terms: D001696:Biomechanical Phenomena; D006801:Humans; D008024:Ligands; D008722:Methods; D008958:Models, Molecular; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013917:Thrombin
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D013917:Thrombin