Multipoint pharmacophores

A difficulty associated with 3D descriptors such as multipoint pharmacophores is the handling of conformational flexibility. Ligands are known to bind to receptors in conformations other than their lowest energy conformations, and there may be many hundreds of accessible conformations for a single molecule. A pharmacophore fingerprint should include all pharmacophore points found in each distinct conformer. This can have both a time implication in generating the conformations and an accuracy implication because the bioactive conformation is typically unknown. 

Multipoint pharmacophore fingerprints have also been used to compare libraries. For example, Pickett et al. [17] have represented libraries by the union of the individual molecular fingerprints and were able to identify regions of multipoint pharmacophore space that were not covered or that were underrepresented. McGregor and Muskal [37,38] developed a similar approach that is based on a low-dimensional pharmacophore space obtained by applying principal components analysis to the three-point pharmacophore representations of the compounds. 

Multipoint pharmacophore approaches to library design are computationally demanding because they require the exploration of conformational space for each product molecule prior to calculating the pharmacophore keys. Thus, Beno and Mason [19] report that the four-point pharmacophore method is currently limited to selecting subsets of a few hundred compounds. 

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