| 摘要 |
Determining a pharmacophore for identifying (e.g. by screening) and designing molecules which possess multi-drug resistance (MDR) modulatory activity. The pharmacophore represents a 3-dimensional aggregate array of positions in space of the field points of a series of molecules having the same, or similar, MDR modulatory activity, and describes regions of positive or negative maxima in the local electrostatic field associated with a molecule, and van der Waals surfaces. A number of lowest energy conformations for each molecule are determined and selected, and interconformational comparisons between conformers of pairs of molecules are carried out and ranked in order of Coulombic overlay energy. A conformational mapping joins pairs of conformers in the top three ranked comparisons (fig. 3), and an optimum cyclic path is determined. This joins all the molecules, with their conformations selected such that the total Coulombic overlay energy over the path is minimised (fig. 4). The field points of these "active" conformations on the cyclic point are combined using an aggregate average method, to generate the pharmacophore. |
