title: Quantitative structure-activity relationships for phosphoramidothioate toxicity in housefly.
abstract: Quantitative structure activity relationships were formulated for a series of phosphoramidothioate (Ace) analogs. Ace II- and Ace IV-induced inhibition of fly-head AChE was influenced by the spatial configuration of the inhibitor. The 3D structure of a potent phosphoramidothioate such as methamidophos was such that its P-O(-)group interacted with the enzyme's 'oxy-anion hole', NH2+ group formed an H-bond with the enzyme's H-bonding site, and leaving group (-S) oriented toward the AChE 'gorge' opening. An alteration in its 3D structure also altered its toxicity. The k(i) for Ace II-induced inhibition of fly-AChE correlated with sterimol indices L1 (the substituent's length), B1 (minimum axis perpendicular to this length), and B3 (-90 degrees to B1) and Ebend. The k(i) for Ace IV-induced inhibition of fly-AChE correlated with dispersion, H-bond donor, and E(dihedral). Thus, the 3D characteristics of a substituent and molecular charge play a key role in the inhibition of fly-head AChE by phosphoramidothioate. LD50 for housefly exposed to Ace I, II, III, and IV analogs was governed by their electronic, topological, steric, and sterimol (steric effects of substituents) properties. Hydrophobic interaction either played a minor role or adversely affected their toxicity in housefly.
authors.affiliation: Department of Veterinary Diagnostic Medicine and Minnesota Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Minnesota, St Paul 55108, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity; D006793:Houseflies / Q000187:drug effects* / Q000201:enzymology; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity*; D007928:Lethal Dose 50; D008956:Models, Chemical; D015394:Molecular Structure; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000633:toxicity*; D063088:Phosphoramides; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D063088:Phosphoramides; C001969:acephate