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∗ Ω) (Eq. (1)). The t_1/2 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 E_bond 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.

Key Words:

• Aging
• Inhibition
• Organophosphates
• Neuropathy target esterase (NTE)
• Reactivation