Aryl Hydrocarbon ReceptorEnvironmental toxins: Estimation of the binding affinity of small molecules towards the Aryl hydrocarbon receptor.
In absence of a three-dimensional structure of the Aryl hydrocarbon receptor, the 140 compounds used in this study were generated in silico and superimposed using the PrGen software. The 4D data set consists of up to four different orientations for the quasi-symmetric molecules. These data were then used as input for multi-dimensional QSAR (software Quasar) where the genetic algorithm is able to identify the bioactive orientation for each ligand molecule. The data set was split into 105 training and 35 test ligands. Quasar allows for the simulation of induced fit and can evaluate multiple scenarios parallel (5D-QSAR). The most recently added sixth dimension (6D-QSAR) allows to simulate different solvation scenarios simultaneously.
Receptor model as generated by Quasar 5.0 (6D-QSAR) with bound aza-PAH.
The simulation yielded a cross-validated r² of 0.810 and a predictive r² of 0.797. The maximal deviation from the experiment corresponds to a factor 17.6 in IC50 for the ligands of the training set and to a factor 12.3 for the ligands of the test set. As for the estrogen receptor, we are now in a position to scan any hypothetical or real compound for potential activity towards the AhR.
Comparison of experimental and predicted IC50 values for the Aryl hydrocarbon receptor
(training set = black, test set = red).