Biomedical Engineering Reference
In-Depth Information
Identifi cation of the structural alert in the ToxTree
Benigni/Bossa model for carcinogenicity and
mutagenicity, available via OpenTax
Figure 2.5
(structural alert for genotoxic carcinogenicity) as shown in Figure 2.5.
Also, the OpenTox models 'IST DSSTox Carcinogenic Potency DBS
Mutagenicity', 'IST Kazius-Bursi Salmonella Mutagenicity' and 'ToxTree:
Structure Alerts for the in vivo micronucleus assay in rodents' are positive.
To identify the structural alerts, we click on the 'Structural Alert for
genotoxic carcinogenicity#explanation' line in the Decision Support
window. In the property tab, the property 'Name' lists the contents of the
#explanation obtained from OpenTox. One can either scroll along the
explanation in the value fi eld of the 'Name' property, or copy and paste
its content to a text editor to identify which structural alert was fi red. For
our compound of interest, it is the presence of a dialkylamine, which
overlaps with the CPDB Signature Alert for Carcinogenicity. The presence
of a dialkylamine is also a structural alert for the ' in vivo micronucleus
assay in rodents' model.
Analyzing the crystal structure of the inhibitor quinazoline 3d bound to
human-TGF-β1 (PDB entry 3HMM [29]), we fi nd that the dimethylamine
is not deeply buried in the binding pocket, but rather exposed, without
making crucial interactions. This is visualized with the Jmol viewer in
Bioclipse in Figure 2.6. The dimethylamino group might therefore be
easily replaceable without markedly affecting the activity of the compound.
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