Journal of Medicinal Chemistry
Combining protein modeling and 6D-QSAR — Simulating the binding of structurally diverse ligands to the estrogen receptorAuthors: Angelo Vedani, Max Dobler and Markus A. Lill
Journal: Journal of Medicinal Chemistry
Biographics Laboratory 3R, Friedensgasse 35, 4056 Basel, Switzerland.
Dedicated to Professor Edgar F. Meyer, mentor and friend, in honour of his 70. birthday.
We present a concept for the simulation of adverse effects triggered by drugs and chemicals in silico. The underlying philosophy combines flexible docking (software Yeti) for the identification of the binding mode(s) and 6D-QSAR (software Quasar) for their quantification. The results obtained for 106 diverse molecules binding to the estrogen receptor (q² = 0.903; p² = 0.885) suggest that our approach is suited for the identification of an endocrine-disrupting potential associated with drugs and chemicals.
Left: Diethylstilbestrol bound to the estrogen receptor (pdb code = 3ERD).
Middle: Diethylstilbestrol bound to the estrogen receptor surrogate.
Right: Comparison of experimental and predicted IC50 values. Green dots mark the ligand molecules of the training set, red dots identify those belonging to the test set; dashed lines mark a factor of five and ten from the experimental value, respectively.