Quantitative structure-activity relationships for organophosphates binding to acetylcholinesterase.

Organophosphates are a group of pesticides and chemical warfare nerve agents that inhibit acetylcholinesterase, the enzyme responsible for hydrolysis of the excitatory neurotransmitter acetylcholine. Numerous structural variants exist for this chemical class, and data regarding their toxicity can be difficult to obtain in a timely fashion. At the same time, their use as pesticides and military weapons is widespread, which presents a major concern and challenge in evaluating human toxicity. To address this concern, a quantitative structure-activity relationship (QSAR) was developed to predict pentavalent organophosphate oxon human acetylcholinesterase bimolecular rate constants. A database of 278 three-dimensional structures and their bimolecular rates was developed from 15 peer-reviewed publications. A database of simplified molecular input line entry notations and their respective acetylcholinesterase bimolecular rate constants are listed in Supplementary Material, Table I. The database was quite diverse, spanning 7 log units of activity. In order to describe their structure, 675 molecular descriptors were calculated using AMPAC 8.0 and CODESSA 2.7.10. Orthogonal projection to latent structures regression, bootstrap leave-random-many-out cross-validation and y-randomization were used to develop an externally validated consensus QSAR model. The domain of applicability was assessed by the William's plot. Six external compounds were outside the warning leverage indicating potential model extrapolation. A number of compounds had residuals >2 or <-2, indicating potential outliers or activity cliffs. The results show that the HOMO-LUMO energy gap contributed most significantly to the binding affinity. A mean training R (2) of 0.80, a mean test set R (2) of 0.76 and a consensus external test set R (2) of 0.66 were achieved using the QSAR. The training and external test set RMSE values were found to be 0.76 and 0.88. The results suggest that this QSAR model can be used in physiologically based pharmacokinetic/pharmacodynamic models of organophosphate toxicity to determine the rate of acetylcholinesterase inhibition.