Pharmacophore-based screening

The pharmacophore-based screening approach has recently been shown to be also very successful for the identification of bio-active natural products. Rollinger et derived a structure-based pharmacophore model on the... 

For the pharmacophore-based screening, a 3-D-pharmaco-phore feature is constmcted by structure-activity relationship analysis on a series of active componnds (26) or is dednced from the X-ray crystal stmcture of a ligand-receptor complex (27). Taking this 3-D-pharmacophore feature as a query structure, 3-D database search can be performed to select the molecnles from the available chemical databases, which contain the pharmacophore elements and may conform to the pharmacophore geometric constraints. Then the selected compounds are obtained either from commercial sonrces or from organic synthesis for the real pharmacologic assays (see Fig. 3). 

A. Pharmacophore"based screening for novel histamine H3"receptor antagonists... 

Pharmacophore-based screening is a virtual screening (VS) method used to automatically evaluate millions of compounds by computer programs [16]. A variety of applications for VS exist. It can be applied to obtain novel lead structures from corporate or commercial databases in early drug discovery, to search virtual... 

Figure 5.4 The AUC value represents the area under the ROC curve and is limited by 0 and 1. Since pharmacophore-based screening mostly results in the selection of a limited number of database molecules that are subjected to...

As mentioned above, vfith respect to model selectivity and database size, hit lists of pharmacophore-based screenings can comprise tens to thousands of small molecules and can be prioritized and filtered by conformer-to-model alignment scores. For further filtering of hit lists, postprocessing methods using criteria for lead- and druglikeness, as well as structural diversity analysis, are available. 

The application of pharmacophore-based screening of chemical databases has led to the discovery of several synthetic leads for promising drug targets. The following two application examples represent a typical structure-based and ligand-based pharmacophore modeling study, respectively. 

Figure 5.8 Structure of a novel nonsteroidal up-HSDl inhibitor (K i = 5.7nM) identified by pharmacophore-based screening (a) and fitted to the modified li5r model (b).

Figure 5.10 Pharmacophore-based screening resulted in three novel CB2 ligands showing low micromolar binding affinities.

The use of pharmacophore-based screening in the field of natural product drug discovery is one of the most recent application areas of pharmacophore models. It has been made possible by the introduction of several natural product databases for VS in... 

Table 5.2 Overview of recent pharmacophore-based screening studies ai... 

Figure 5.11 Biologically active natural products identified by pharmacophore-based screening.

Staphylococci are responsible for most of the nosocomial infections. Since these bacteria are resistant to several antibiotics, there is an urgent need for novel drugs against Staphylococci infections. Quorum-sensing inhibitors that block the cell-to-cell communication between Staphylococci and thereby inhibit their virulence could represent an alternative to antibiotics. A pharmacophore-based screening retrieved hamamelitannin (7, Figure 5.11) from the bark and leaves of Hamamelis virginiana. 

Schuster, D., Nashev, L.G., Kirchmair, J., Laggner, C., Wolber, G., Langer, T., and Odermatt, A. (2008) Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries. Journal of Medicinal Chemistry, 51, 4188 199. 

Figure 15.5 Chemical structures of nine selected and experimentally tested PRMTl hits from the pharmacophore-based screening.

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