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Bradykinin B₂ Receptor

Drug design — vasodilation/bronchioconstriction: Estimation of the binding affinity of small molecules towards the Bradykinin B₂ receptor.

In absence of a three-dimensional structure of the Bradykinin B₂ receptor, the 186 compounds used in this study were generated in silico and superimposed using the Simposar software, a new tool developed at the Biographics Laboratory allowing for a flexible ligand alignment. These data were used as input for multi-dimensional QSAR (software Quasar and Raptor) where the genetic algorithm is able to identify the bioactive orientation for each ligand molecule.

Receptor model as generated by Quasar 5.0 (6D-QSAR) with the most potent ligand of the series shown.

The data set was split into 147 training and 39 test ligands. Quasar allows for the simulation of induced fit and can evaluate multiple scenarios parallel (5D-QSAR). The simulation yielded a cross-validated r² of 752/0.815 and a predictive r² of 0.784/0.853. The maximal deviation from the experiment corresponds to a factor 14.1 in IC₅₀ for the ligands of the training set and to a factor 9.6 for the ligands of the test set.

Comparison of experimental and predicted IC₅₀ values for the Bradykinin B₂ receptor
(training set = black, test set = red).

Reference: J. Chem. Inf. Model. 2006, 46, 2135–2145. View Abstract