Patent DE-102005061270-A1 (DE)
Title: Procedure for structure-based virtual screening of biologically active compounds, comprises categorizing and/or sorting the compounds in catalogue on the basis of their physicochemical and/or geometrical and/or structural characteristics
Inventor: LEMMEN CHRISTIAN
IPC: G16C20/64
Filed: 2005-12-20
Abstract: The procedure for sub-linear structure-based virtual screening of biologically active compounds (molecules), comprises categorizing and/or sorting (1) the compounds in catalogue on the basis of their physicochemical and/or geometrical and/or structural characteristics, determining (2) the characteristics of a biological target, determining (3) the catalogue or the parts of the catalogue, which match the determined characteristics of the target, and screening (4) of the compounds in the parts of the catalogue against the target. The procedure for sub-linear structure-based virtual screening of biologically active compounds, comprises categorizing and/or sorting (1) the compounds in catalogue on the basis of their physicochemical and/or geometrical and/or structural characteristics, determining (2) the characteristics of a biological target, determining (3) the catalogue or the parts of the catalogue, which match the determined characteristics of the target, and screening (4) of the compounds in the parts of the catalogue against the target. The characteristics of the target represent the structure of the bonding site of a receptor or a relative orientation in relation to the target of the active compounds or a biological activity of the target. The characteristics of the target and/or the compounds are described by descriptors (target- and/or molecule descriptor). The descriptors are sorted according to their characteristic values and are administered with standardized index structures such as B-trees. The descriptors describe the physicochemical and/or geometrical and/or structural characteristics of triplets of functional groups of compounds and/or a target and direction-dependent conditions or preferred orientation of functional groups of a compounds and/or a target with respect to atomic coordinates. The preferred orientations of a functional group in the triplet are described by centering of a local coordinate system in the functional group and alignment of the coordinate system with respect to other functional groups. The preferred orientation of a functional group relative to a local coordinate system, is described by Euler angles with respect to the axes of the local coordinate system. Areas for the side lengths are defined by triangles and Euler angles, which are considered within the characteristics of compounds-descriptor as compatible to the conditions of a target-descriptor. The compounds are divided into fragments and are examined and/or scanned with respect to their conformation to identify the relative spatial position of functional groups in the compounds and/or in the fragments and to identify the spatial position of interaction centers of the compounds and/or interaction centers of the fragments. The fragment-interaction triangles for each fragment-conformers are formed by triplets of interaction centers of the fragments and describe the physicochemical and/or geometrical and/or structural characteristics of fragment-conformers using a molecule-descriptor. Favorable interaction centers are looked into the binding sites of the receptor and/or target for functional groups of compounds. A set of interaction triangles for positions or places of the target, is defined by triplets of the site interaction centers, and the descriptors of the interaction triangles describe the required fragments-interaction centers (FIAC) types, the FIAC intervals in pairs and the FIAC interaction directions for a fragment, whose interaction centers are overlaid with the site interaction centers of the interaction triangles of the target. All positions- or site-interaction triangles of the receptor are processed, and the conditions of each interaction triangle of the target under the consideration of a suitable tolerance range in positive and negative direction, are converted into an index range-inquiry of a table of the fragment-interaction triangles of the compounds. Each target stored in a hit-list is shifted by an algorithm into a placement of the fragment-conformers or complete molecule in the bonding site of the receptor. An examination of steric fits for each placement of each fragment-conformer in the binding site of the receptor, are carried out and the bonding affinity for each placement is evaluated. The fragments, which belong to which compounds are evaluated, and if necessary the combinations of placements of different fragments of the same compounds are identified, which is realized with compounds-conformation. The measure of the affinity of placed and evaluated fragments, is used in order to set up a ranking of the compounds, which shows a valid placement. The catalogue is stored in a virtual library of a data base of a computer program. One of the target descriptors is defined in such a way that it is used for the inquiry of the stored catalogue. An independent claim is included for a computer program with program code for carrying out the procedure for structure-based virtual screening of biologically active compounds.