Biomedical Engineering Reference
In-Depth Information
O
OH
O
Br
3.13
K i = 0.9 nM
FIGURE 3.7
Compound 3.13 i tted to the pharmacophore model.
4500-fold higher than that of the parent l avone 3.1 as a result of the addition of only three properly
placed substituents. Compound 3.13 is shown i tted to the i nal pharmacophore model in Figure 3.7.
3.5 DATABASE SEARCHING USING THE PHARMACOPHORE MODEL
To identify new classes of compounds, which may bind to the BZD site, the pharmacophore model in
Figure 3.6 was used for database searching in CATALYST. Two different compound databases, the
Maybridge database (Maybridge Chemical Company) with approximately 47,000 compounds and
the Available Chemical Directory (ACD) database (MDL Information Systems, Inc.) with approxi-
mately 250, 000 compounds were searched. In order to search a database using a 3D-pharmacophore
model, the compounds in the database, which are 2D structures has to be converted to 3D structures
and a set of conformations for each compound has to be generated. The conformations can either be
generated in advance or for some programs during the search. In CATALYST, a set of conforma-
tions for each compound in the database is generated in advance. When a pharmacophore model is
used to search a database, compounds i tting all or some of the pharmacophore elements are identi-
i ed. Such compounds are called “hits.” In the present case, it is required that all pharmacophore
elements must to some degree be i tted to give a hit. In the search procedure all compounds are
given a i t value indicating how well they i t the pharmacophore elements of the model. After the
search, a list of hits ranked according to their i t value is available.
As described in Sections 3.4.2 and 3.4.3, exclusion spheres and a vdW shape may be used in a
pharmacophore model to represent the dimensions of the receptor binding cavity. This is of high
importance for database searching in order to keep the number of hits to a manageable size.
The difference between an exclusion sphere and the vdW shape is that no ligand is allowed
to touch an exclusion sphere without a severe penalty, whereas a ligand may be somewhat larger
or smaller than the shape without a penalty. In the present case, ligands with vdW volumes 30%
smaller or 10% larger than the volume of the shape are allowed.
When the two databases were searched using the pharmacophore model in Figure 3.6, 22 hits in
the Maybridge database and 76 hits in the ACD database were obtained. (It should in this context be
mentioned that these database searches are very fast, using less than 30 min per database.) Among
the 98 hits, i ve compounds of the highest ranking hits with a signii cant diversity of the molecular
structures were selected and purchased. The highest afi nity of these compounds was the 4-quinolone
derivative 3.14 ( K i = 122 nM) shown in Figure 3.8. As also shown in the i gure, this compound is
 
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