Journal of the American Chemical Society

Quasi-atomistic receptor surface models : A bridge between 3-D QSAR and receptor modeling

Authors: Angelo Vedani, Max Dobler; and Peter Zbinden
Journal: Journal of the American Chemical Society
Year: 1998
Issue: 120
Pages: 4471–4477

Biographics Laboratory 3R, Missionsstrasse 60, 4055 Basel, Switzerland.
Laboratory for Organic Chemistry, ETH Zürich, 8092 Zürich, Switzerland.

A "quasi-atomistic receptor model" refers to a three-dimensional receptor surface, populated with atomistic properties (hydrogen bonds, salt bridges, hydrophobic particles, and solvent) mapped onto it. In contrast to other 3D-QSAR approaches, an algorithm developed at our laboratory allows for the adaptation of the receptor-surface defining envelope to the topology of the individual ligand molecules. In addition, it includes H-bond-flip-flop particles which can simultaneously act as H-bond donors and H-bond acceptors toward different ligand molecules, binding to the surrogate within a pharmacophore hypothesis. Such particles mimic amino-acid residues able to engage in differently directed H-bonds at the true biological receptor. Ligand-receptor interaction energies are evaluated using a directional force field for hydrogen bonds and salt bridges. Based on a series of ligand molecules with individually adapted receptor envelopes, Quasar allows to generate a large family of quasi-atomistic receptor models using a genetic algorithm combined with cross-validation.

Our concept has been used to derive semi-quantitative structure-activity relationships for the ß2-adrenergic, aryl hydrocarbon, cannabinoid, neurokinin-1, and sweet-taste receptor as well as for the enzyme carbonic anhydrase. The receptor surrogates for these systems are able to predict free energies of ligand binding for independent sets of test ligand molecules within 0.4 to 0.8 kcal/mol (RMS) of the experimental value.