Pharmacophores conformational analysis

Conformational analysis. Pharmacophore discovery inherently involves the 3D structure of molecules and, by necessity, goes beyond merely the low-energy conformation. 

Constrained Search and the related approach of SCAMPI both integrate the conformational analysis closely with the pharmacophore discovery. This has the advantage that the sampling of conformational space can be more focused on key regions. With both Catalyst and DANTE, conformational analysis was explicitly kept separate, in the latter to allow one to take advantage of any innovations in conformational analysis tools. And, indeed, there continues to be a steady flow of new approaches in conformational analysis—pharmacophore discovery is critically dependent on high-quality exhaustive conformational analysis. Based on our experience thus far, we cannot conclude that either approach is superior (integrated vs. external). Furthermore, a consensus has not yet been reached on the optimal manner to perform conformational search as needed by pharmacophore discovery. This will continue to be a fruitful area of research. 

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Figure 5.6. Overview of the Gridding and Partitioning (GaP) procedure as applied to monomers, exemplified using phenylalanine as a potential primary amine. This molecule thus contains two pharmacophoric groups (the aromatic ring and the carboxylic acid). During the conformational analysis the locations of these pharmacophoric groups are tracked within a regular grid. See color insert. [Reproduced from A. R. Leach and M. M. Hann, Drug Discovery Today, 5, 326-336 (2000),...

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