A quantitative structure–activity relationship investigation into agonist binding at GABAC receptors

The quantitative structure–activity relationship (QSAR) model constructed in this work represents the first quantitative investigation into agonist binding at GABAC receptors. This model is based upon the three-dimensional structures of (g-aminobutyric acid (GABA) and 12 other biologically active GABA analogues. These structures are obtained by geometry optimization and conformational exploration at MP2/6-31CG* within the conductor-like screening solvation model (COSMO). The biological activity data are obtained from previous twoelectrode voltage clamp electrophysiological studies on recombinant GABAC r1 receptors expressed in Xenopus laevis oocytes. A QSAR model to predict GABAC agonist binding is constructed from molecular superposition data, generated by least-squares superposition of the stable aqueous phase conformations of GABA and its known biologically active analogues to the bioactive conformation of TACA, the most potent GABAC receptor agonist. A significant relationship is found between the root-mean-squared deviation in atomic position for the stable conformer of each GABA analogue most closely fitting the template TACA structure and the natural log of the normalized biological activity (RZ0.91, p!0.0001), On the basis of molecular superposition and QSAR results, a pharmacophore model describing three-dimensional features and key interactions at the GABAC receptor binding site is proposed. As there exists no direct experimental knowledge of structure of the GABAC binding site, this approach provides a feasible and reliable alternative to gain insight into its three-dimensional structure. q 2005 Elsevier B.V. All rights reserved.