Molecular modeling of mono- and bis-quaternary ammonium salts as ligands at the alpha 4 beta 2 nicotinic acetylcholine receptor subtype using nonlinear techniques

• Published in: The AAPS journal 2005-01, Vol.7 (3), p.E678-E685
• Main Authors: Ayers, Joshua T, Clauset, Aaron, Schmitt, Jeffrey D, Dwoskin, Linda P, Crooks, Peter A
• Format: Article
• Language: English
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/aapsj070368

The neuronal nicotinic acetylcholine receptor (nAChR) has been a target for drug development studies for over a decade. A series ofmono- andbis-quaternary ammonium salts, known to be antagonists at nAChRs, were separated into 3 structural classes and evaluated using both self-organizing map (SOM) and genetic functional approximation (GFA) algorithm models. Descriptors from these compounds were used to create several nonlinear quantitative structure-activity relationships (QSARs). The SOM methodology was effective in appropriately grouping these compounds with diverse structures and activities. The GFA models were also able to predict the activities of these molecules. Charge distribution and the hydrophobic free energies were found to be important indicators of bioactivity for this particular class of molecules. These QSAR approaches may be a useful to screen and selectin silico new drug candidates from larger compound libraries to be further evaluated in in vitro biological assays.