Pharmacophore constraint

Hindle, S.A., Rarey, M., Buning, C., and Lengauer, T. Flexible docking under pharmacophore constraints. 

Fig. 6. Chemotype enrichment rates using a variety of structure-based virtual screening algorithms and constraint settings for CDK2. DOCK search incorporating target class critical pharmacophore constraints denoted by the mark. Adapted from ref. 70.

Virtual screening often benefits from an expert bias which helps focus on more desirable results, given in the form of additional information. A point in case is docking under pharmacophore constraints [37] or the concept of relative pharmacophores with a special internal reference point [38]. Yet another application for a directionally biased compound comparison is the selection of chemical reagents where functional attachment points are aligned and pharmacopho-ric features are examined relative to this point of reference by a procedure termed GaP [39]. Other concepts which try to describe combinatorial products in terms of their educts and need a special reference point are shape-based To-pomers [24] and pharmacophore based OsPreys [40]. 

Finally, while pharmacophore and docking methods are still two distinct methods for VS, the distance between them appears to be growing smaller structure-based pharmacophore methods are trying to include more and more information about the binding site (Sections 3.4.2 and 3.4.3), while some docking programs have successfully incorporated pharmacophore constraints, which we discuss in the next section. 

The ChK-1 crystal structure (Fig. 16) was proto-nated at crystallization pH. Active site contained all the residues within 6.5 A of the bound inhibitor. Essential pharmacophore constraints for the Cys87 (backbone NH) and Glu85 (backbone CO) residues were given (Figs. 17 and 18). 

Thus, in this case, global similarity-based LEVS methods successfully identified a new inhibitory chemotype that would not have been found had the known pharmacophore constraints taken into account. 

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