Quantitative structure-activity relationships for phosphoramidothioate toxicity in housefly

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°to B₁) and E(bend). 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. Copyright (C) 1999 Elsevier Science Inc.