A. Vedani et al., Genetic algorithms in 3D-QSAR: The use of multiple ligand orientations forimproved predictions toxicity., ALTEX-AL TI, 16(3), 1999, pp. 142-145
In a recent article in this journal, we discussed the application of a 3D-Q
SAR technique to the prediction of the toxicity of dibenzodioxins, dibenzof
urans, and biphenyls (Vedani et al., 1999a). The use of such methods is leg
itimate because there is strong evidence that the toxicity is mediated by t
he Aryl hydrocarbon (Ah) receptor; a regulatory element involved in the mam
malian metabolism of xenobiotics. In an extention to a concept developed at
our laboratory (Vedani et al, 1998), ute now show that safer predictions a
re possible if instead of a single - and therefore, necessarily biased - as
sumption about the mutual orientation of the toxins, an ensemble of possibl
e orientations is used for model construction. The contribution of a single
entity within this ensemble to the toxin-receptor interaction energy is de
termined by a Boltzmann criterion. While in the single-orientation model tw
o of the 26 toxins of an external test set were predicted false positive or
false negative, all test substances are correctly predicted in the multipl
e-orientation model - including lip to four different orientations per mole
cule - within a factor 10 of the experimental binding affinity.
These results demonstrate that 3D-QSAR techniques based on a genetic algori
thm can be used to predict the toxicity of chemical and pharmacological sub
stances "in compute" if a receptor-mediated mechanism can be assumed. Conse
quently, the method can be used in toxicological screening assays, thereby
replacing stressful tests on animals.