title: QSAR for the organophosphate-induced inhibition and 'aging' of the enzyme neuropathy target esterase (NTE).
abstract: QSAR was devised for the neuropathy potency of various organophosphate (OP) compounds. The neuropathy-target-esterase (NTE) inhibition data were either obtained from the literature for a number of OP compounds or were determined experimentally for methamidophos, acephate, coumaphos and EPN. Aging Index that determined whether or not an OP would age NTE, correlated with molecular depth (MD) and the index density* dipole-moment (density* omega) (Eq. (1)). The t1/2 values that represented the time (min) during which 50% of the OP-inhibited brain NTE undergoes 'aging', correlated with the topological indices Dif3 and 1/Dif4 (Eq. (2)). Log10I50 for AChE that determined the OP concentration causing 50% inhibition in AChE activity, correlated with EBOND and Charge-1 (Eq. (3)). Log10I50 for NTE correlated with 1/HS2 and H-Bonding (Eq. (4)). The (Log10I50NTE)/(Log10I50AChE) ratio that determined an OPs neuropathy potential relative to its cholinergic toxicity potential, correlated with log P and Log10Polarity (Eq. (6)). Equation (3) accurately predicted AChE inhibition by methamidophos, coumaphos and EPN, but not by acephate. Equations (1), (2), (4)-(6), accurately predicted their respective biological indices. Therefore, it is proposed that the QSAR models developed in this study may accurately predict the neuropathy potential of OP compounds. The only exception is Eq. (3) that did not accurately predict the acephate-induced inhibition of AChE, possibly because acephate and other OPs inhibit the enzyme by distinct mechanisms.
authors.affiliation: Department of Veterinary Diagnostic Medicine, College of Veterinary Medicine, University of Minnesota, St Paul Campus, 1333 Gortner Ave., St Paul, MN 55108, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity*; D009447:Neuroblastoma / Q000201:enzymology; D009943:Organophosphorus Compounds; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D014407:Tumor Cells, Cultured
chemical_list: D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase