title: Development of quantitative structure activity relationships for the binding affinity of methoxypyridinium cations for human acetylcholinesterase.
abstract: Among the most toxic substances known are the organophosphorus (OP) compounds used as pesticides and chemical warfare agents. Owing to their high toxicity there is a number of efforts underway to develop effective therapies for OP agent exposure. To date all therapies in use treat inhibited acetylcholinesterase (AChE), but are ineffective for the treatment of inhibited AChE, which has undergone a subsequent hydrolysis process, referred to as aging. Toward developing a therapy for treating victims of OP intoxication in the aged state we have developed Quantitative Structure-Activity Relationships (QSARs) based on the AM1 semiempirical quantum mechanical method using the program, CODESSA (COmprehensive Descriptors for Structural and Statistical Analysis). Using this methodology we obtained a multiple correlation QSAR equation which gave R(2)=0.9359 for a random training set of 38 ligands and R(2)=0.9236 for prediction on a random test set of 9 ligands.
authors.affiliation: Department of Chemistry, William Jewell College, 500 College Hill, Liberty, MO 64068, United States. Electronic address: morrillj@william.jewell.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Morrill
authors.affiliation: Department of Chemistry, University of Iowa, E331 Chemistry Building, Iowa City, IA 52242-1294, United States.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Topczewski
authors.affiliation: Department of Chemistry, University of Iowa, E331 Chemistry Building, Iowa City, IA 52242-1294, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lodge
authors.affiliation: Department of Chemistry, University of Iowa, E331 Chemistry Building, Iowa City, IA 52242-1294, United States.
authors.forename: Nilanthi
authors.initials: N
authors.lastname: Yasapala
authors.affiliation: Department of Chemistry, University of Iowa, E331 Chemistry Building, Iowa City, IA 52242-1294, United States. Electronic address: ian.prout@thermofisher.com.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Quinn
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D002801:Cholinesterase Reactivators / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D010755:Organophosphates / Q000737:chemistry; D025341:Principal Component Analysis; D011485:Protein Binding; D011726:Pyridinium Compounds / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase
keywords: AChE binding affinity; AM1; Methoxypyridinium cations; QSAR