Mechanistic insight into acetylcholinesterase inhibition and acute toxicity of organophosphorus compounds: a molecular modeling study.

Acute toxicity of organophosphorus (OP) compounds results mainly from irreversible acetylcholinesterase (AChE) inhibition; however OP toxicity frequently hinges on prior biotransformations that produce toxic metabolites. To account for both precursor metabolic effects and primary AChE inhibition, we included absorption, distribution, metabolism, excretion (ADME) effects, ligand binding, and reactive AChE phosphorylation and aging in a detailed but computationally expedient phenomenological toxicity model. Ligand negative accessible surface area (NASA) was used as a generic ADME descriptor, while relevant metabolic, phosphorylation, and aging reactions were assessed via quantum chemical enthalpy calculations, and the binding affinity of the Michaelis complex was quantified via Comparative Molecular Field Analysis (CoMFA). The resulting model correlates very well (R2 = 0.90) with experimental acute toxicity measurements and provides useful mechanistic insight into the underlying toxicity. Model predictivity was validated by leave-one-out cross-validation (Q2 = 0.82). The Michaelis binding affinity descriptor has the largest weight in our model, but subsequent covalent inhibition and prior ADME effects also exhibit significant effects.