title: Molecular modeling of mono- and bis-quaternary ammonium salts as ligands at the alpha4beta2 nicotinic acetylcholine receptor subtype using nonlinear techniques.
abstract: The neuronal nicotinic acetylcholine receptor (nAChR) has been a target for drug development studies for over a decade. A series of mono- and bis-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 select in silico new drug candidates from larger compound libraries to be further evaluated in in vitro biological assays.
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Ayers
authors.forename: Aaron
authors.initials: A
authors.lastname: Clauset
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Schmitt
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D008024:Ligands; D008958:Models, Molecular; D017711:Nonlinear Dynamics; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry*
chemical_list: D008024:Ligands; D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2