Assessing oxime reactivation efficacy using principal component analysis: Insights from nerve agents inhibited human butyrylcholinesterase.

Background and purpose: The toxicity of organophosphorus compounds (OPs) and related nerve agents (NAs) impairs the cholinergic system via irreversible inhibition of acetylcholinesterase (AChE) activity by phosphylation of the catalytic serine. Reactivation of the enzyme activity largely depends on the structural compatibility between the enzyme, an oxime reactivator, and the specific OP compound. Experimental approach: For this study, we used our recently published data on the reactivation of human butyrylcholinesterase inhibited by the NAs sarin, cyclosarin, tabun and VX, using a library of 115 oximes. We compared these results with oximes' ADME (absorption, distribution, metabolism, and excretion) parameters relevant to central nervous system activity using principal component analysis (PCA). PCA facilitated the examination of these relatively large datasets by increasing interpretability while minimizing information loss. Key results: Three components with eigenvalues above 1 resulted in 72 % of the cumulative proportion of variance and described 27 variables. PC1 created transformed data that had negative values for most oximes with high reactivation potential, while showing large positive values for oximes with moderate and low efficacy. Distribution of 27 loadings, representing 27 variables, produced a set of 9 positive and 18 negative loadings representing negative and positive data correlation. The efficacy of oxime reactivation was highly correlated with the parameters describing its structure: molecular weight, rotational bonds, molecular volume, and molecular surface area. Conclusion: A large dataset was efficiently analysed by maximizing the preservation of variability and generating new, uncorrelated variables. To our knowledge, this study is the first to apply PCA to assess oxime's reactivation efficacy, thus providing insights into the relationships between oxime properties and their efficacy in restoring OP-inhibited cholinesterase activity.