3D-QSAR using 'multiconformer' alignment: The use of HASL in the analysis of 5-HT1A thienopyrimidinone ligands

The observed 5-HT1A and alpha(1)-adrenergic receptor (alpha(1)-AR) receptor binding properties of a series of 23 thienopyrimidinones were used to deve lop HASL 3D-QSAR models. A single, low energy conformer of the most active analogue in the series, which was consistent with NMR structural studies, w as chosen as a template molecule. Alignments of all the molecules to the te mplate were provided by an Amber/MM2 superposition force field. In this man ner, each molecule was represented by five separate low energy conformers w hich were subsequently used in the generation of HASL 3D-QSAR models. Model s derived from multiple conformers were found to exhibit enhanced predictiv ity compared to models based on single, low energy conformers. In addition, the use of contour imaging of HASL multi-conformer model interactions was found to lead to a more consistent interpretation of those molecular featur es most significant for 5-HT1A receptor binding.