Conclusions

To our knowledge, this is the first application of PC analysis to evaluate a library of oximes for efficacy in reactivation of ChE inhibited by OP compounds. Our study confirms the benefit of the PCA method, as it preserves as much variability as possible and translates it into finding new mutually uncorrelated variables that are linear functions of those in the original reactivation dataset. In addition to evaluating oxime efficacy for individual OP compounds (GA, GB, GF and VX), the analysis was expanded to include pharmacokinetic parameters relevant to drug design and BBB permeability, enabling assessment of potential CNS activity. Moreover, structure-activity relationship analysis in the development of novel active compounds with a new scaffold and advanced ADME properties is a widely accepted method [26].

The resulting variable loadings and their magnitudes highlighted significant pharmacokinetic parameters for evaluating oxime efficacy across all four OP compounds. The benefit of simultaneous four OP compound PC analysis over individual OP compound PC analysis lies in the mutual comparison of OP-related kinetic parameters with the addition of pharmacokinetic parameters. A limitation of the individual OP compound PC analysis is the relatively low proportion of kinetic parameters relative to the number of pharmacokinetic parameters included in the analysis, resulting in a very similar distribution of transformed data among OP compounds.

The primary advantage of the joint four OP compounds PC analysis is the ability to identify a single oxime compound, the so-called universal reactivator, that effectively reactivates ChEs inhibited by multiple OP compounds. This is evident in GA reactivation, where many oximes from the studied library were ineffective reactivators. Nevertheless, those that were effective also showed strong reactivation potential of GB-, GF- and VX- BChE conjugate.

BChE also acts as a natural scavenger of OP compounds. Therefore, its reactivation is important for the development of a pseudo-catalytic system in which cycles of BChE inhibition and reactivation with an effective, versatile oxime would degrade OP compounds in a patient's bloodstream prior to inhibition of synaptic AChE. Besides, it would be advantageous if this oxime crossed the BBB and acted as an effective reactivator of BChE in the CNS, thereby protecting synaptic AChE.