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. Author manuscript; available in PMC: 2010 Oct 8.
Published in final edited form as: J Med Chem. 2009 Oct 8;52(19):6107–6125. doi: 10.1021/jm901096y

Figure 7.

Figure 7

The overall procedure begins with an initial alignment hypothesis, as shown in Figure 2, which is used to generate initial alignments of all training ligands, possibly using multiple approaches (panel A shows a single alignment for each active training ligand). The initial alignments of active ligands are used to produce a large number of molecular probes that interact well with at least one pose of one active ligand (panel B, with hydrophobic probes shown without hydrogens for clarity). A subset of the probes are chosen to optimize concordance with activity (panel C, thick sticks). These identify the known pharmacophore, characterized by interactions with a donor (blue arrow), a charged acceptor (red arrow), and hydrophobic interactions (gray arrows). Additional probes are added back in order to provide “coverage” of the entire possible pocket (probes shown with thin sticks). Panel D shows the final optimized pocket (atom color) along with the initial probe positions (blue).