Journal of Medicinal Chemistry

Impact of induced fit on ligand binding to the androgen receptor: A multidimensional QSAR study to predict endocrine-disrupting effects of environmental chemicals

Authors: Markus A. Lill, Fabienne Winiger, Angelo Vedani and Beat Ernst
Journal: Journal of Medicinal Chemistry
Year: 2005
Issue: 48
Pages: 5666–5674

Institute of Molecular Pharmacy, University of Basel, CH-4056 Basel, Switzerland and Biographics Laboratory 3R, CH-4056 Basel, Switzerland.

We investigated the influence of induced fit of the androgen receptor binding pocket on free energies of ligand binding. Based on a novel alignment procedure using flexible docking, molecular dynamics simulations and linear-interaction energy analysis, we simulated the binding of 119 molecules representing six compound classes. The superposition of the ligand molecules emerging from the combined protocol served as input for Raptor, a receptor-modeling tool based on multidimensional QSAR allowing for ligand-dependent induced fit. Throughout our study, protein flexibility was explicitly accounted for. The model converged at a cross-validated r² = 0.858 (88 training compounds) and yielded a predictive r² = 0.792 (26 test compounds), thereby predicting the binding affinity of all compounds close to their experimental value. We then challenged the model by testing five molecules not belonging to compound classes used to train the model: the IC50 values were predicted within a factor of 4.5 compared to the experimental data. The demonstrated predictivity of the model suggests that our approach may well be beneficial for both drug discovery and the screening of environmental chemicals for endocrine disrupting effects — a problem that has recently become a cause for concern among scientists, environmental advocates and politicians alike.


Left: Local induced fit simulated with MD demonstrates that the additional volume occupied by the benzoate portion of DHT benzoate (green) is well accomodated. DHT (cyan) binding is shown as reference.

Center: Superposition of the molecules representing the different compound classes (one each) used in our QSAR study. The binding pocket of the experimental androgen receptor-DHT complex displays steric clashes when used as rigid template for docking.

Right: Comparison of predicted and experimental binding affinities for the 119 molecules used in our study. Training set (dark green/light green; model building) and test set (red/orange; model validation). Threshold compounds are shown in light green and orange, respectively.