4-Point pharmacophores virtual screening

Another group has evaluated self-organizing maps [63] and shape/ pharmacophore models [64]. They developed a new method termed SQUIRREL to compare molecules in terms of both shape and pharmacophore points. Thus from a commercial library of 199,272 compounds, 1926 were selected based on self-organizing maps trained on peroxisome proliferator-activated receptor a (PPARa) "activity islands." The compounds were further evaluated with SQUIRREL and 7 out of 21 molecules selected were found to be active in PPARa. Furthermore, a new virtual screening technique (PhAST) was developed based on representation of molecules as text strings that describe their pharmacophores [65]. 

Mason, J.S. and Cheney, D.L. Library design and virtual screening using multiple 4-point pharmacophore fingerprints. Pac. Symp. Biocomput. 1999, 4, 456-467. 

Fig. 15.25 Partial display of virtual screen of conformational ensemble of " 75 000 structure library based on multiple templates. A display of fitness scores to a three-point pharmacophore model provides initial signs of similarity of a library design to that model. Subsequent virtual screening against a more stringent four-point pharmacophore model further highlights potentially useful library designs.

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]. 

The multiple potential pharmacophore key calculated from a ligand can be compared to the multiple potential pharmacophore key of complementary site-points in its target binding site. This provides a novel method to measure similarity when comparing ligands to their receptors, with applications such as virtual screening and structure-based combinatorial library design. 

J.S. Mason and D.L. Cheney, Library Design and Virtual Screening Using Multiple 4-Point Pharmacophore Fingerprints, Pacific Symposium on Biocomputing, 2000, 5, 573-584. 

The structure based virtual screening process includes also the use of some keywords. With these keywords FLAP fdters out matches and keeps them only if they make sense in terms of binding site shape. FLAP can also allow additional binding site volume (cavity expansion, useful when the protein structure under investigation is an homology model) and with the use of regions (definition of a sphere within each pharmacophore needs to have at least one point) or selection of a probe (enforcing a particular feature to be present in the calculated pharmacophores) certain constraints can also be added. 

If the target of the ligands under investigation is known, another possible approach is to compare ligands using the shape of the protein as a shape constraint and features in the protein cavity as additional constraints. As in the case of structure based virtual screening, keywords are used such as regions to define a sphere within which each pharmacophore needs to have at least one point, and the selection of a particular probe. 

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