Interactive predictive toxicology with Bioclipse and OpenTox - Open Source Software in Life Science Research - page 42

Crystal structure of human TGF- β 1 with the inhibitor
quinazoline 3d bound (PDB-entry 3HMM). The
dimethylamino group of TCMDC-135308 is bound to
the carbon atom of quinazoline 3d highlighted by the
white arrow, thus pointing toward the water-exposed
side of the binding pocket. The image was generated
from the 3HMM crystal structure, hiding all water
molecules, using the Jmol editor in Bioclipse

Figure 2.6

However, as we do not know the exact target protein in P. falciparum ,
we cannot exclude that the dimethylamino group is important for the
activity or selectivity of the compound. Therefore, we try to replace it
with a bioisosteric group, the simplest one being a methoxy group.
In the Bioclipse compound window, we modify the structure of
TCMDC-135308 by renaming the nitrogen atom of the dimethyl amino
group to oxygen, and deleting one of the methyl groups of the former
dimethyl amino group.
Re-running all predictions, we fi nd that there are no CPDP signature
alerts anymore, and that the OpenTox Benigni/Bossa rules predict the
modifi ed compound to be negative for both genotoxic and non-genotoxic
carcinogenicity (Figure 2.7). Also the 'IST DSSTox Carcinogenic
Potency DBS Mutagenicity' and 'IST DSSTox Carcinogenic Potency DBS
Mouse' models are now negative. The OpenTox model for the in vivo
micronucleus assay is still positive because of the presence of two
hydrogen-bond acceptors that are three bonds apart. Also the OpenTox
'IST DSSTox Carcinogenic Potency DBS SingleCellCall' and 'IST Kazius-

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