Direct approaches, pharmacophore modeling

Pharmacophore profiles are defined that represent the set of all the pharmacophores found across the conformers of a series of conformers or series of molecules. Each pharmacophore added to the profile has to be unique. This profile will help in showing the spread of pharmacophores across the conformational space of a molecule or a series of molecules. No sum of the exhibited pharmacophores or normalization is done. There is no direct graphical representation of pharmacophore models. The pharmacophores can be saved to a file in CSV format that can be imported into a MySQL or Oracle database. This approach permits the use of standard SQL queries to extract common pharma-... 

One of the difficulties with this type of approach is that the quality of the results depends directly on the quality of the initial pharmacophore model, which can sometimes prove challenging. A particular hazard is that active compounds can have different binding modes, even in a closely related series of inhibitors. This algorithm partially addresses that problem, since it does not take as a fundamental assumption that all molecules bind in the same orientation, however further tools to identify alternative binding modes would be helpful. Overall it shows potential to be a powerful tool to direct library design. 

The ensemble distance geometry pharmacophore modeling approach of Sheridan et al. (145) provides the most direct and efficient method for... 

The availability of the three-dimensional structure of the protein complex allows structure-driven drug discovery approaches. In this case, a pharmacophore model is first established. This corresponds to identifying the interactions that take place at the interface and which contribute most to AG. The importance of these interactions can be validated by site-directed mutagenesis or, when possible, by the use of peptides. Once these interactions are validated, molecules containing chemical groups mimicking these key interactions are selected from compound libraries and tested. Very often these initial molecules are not optimal (e.g., they do not make all the key contacts) and they must be modified to enhance their potency. This is done, for example. 

Although the solid-phase formation of this clinically valuable pharmacophore occurred with high cis selectivity, the diastereoselectivity induced by the asymmetric center of the amino acid was only very moderate. Induction could be achieved, however, with an optically active ketene. By using this approach, a model library of 25 p-lactams of type 111/112 was initially formed in higher than 80% purity, and this chemistry was subsequently used to generate a combinatorial library of thousands of 3,4-bis-substituted 2-azetidinones of sufficient purity to be directly submitted for bioassays. 

Figure 3 Structural alignments with discrete properties. Methods are based on discrete properties using the DG algorithm (1) or clique-detection (11) as implemented in distance comparisons (DISCO), and Apex-3D. The structure representation, based on discrete properties, resorts to one atomic descriptor (I), usually the atom type, or multiple atomic or site descriptors (II). In the first method (I), the conformational analysis is restricted to the generation of molecular geometries which allow a common arrangement of selected phaimacophoric moieties present in a rigid compound used as template. In the second method (II), the conformational analysis procedure may involve a systematic enumeration of all the possible conformadons for each ligand. The search similarity is directed towards the confirmation of a predefined pharmacophore postulated by the modeler or from some classical SAR in the case of the active analog approach (1), or the automated identification of pharmacophores and bioacdve conformations (II)...

---