Permeability prediction for zwitterions via chromatographic indexes and classification into 'certain' and 'uncertain'

Background: The development of zwitterions to a drug is likely to be more challenging than compounds of other charge types. Results: Two chromatographic indexes (log k'80 PLRP-S and log K_W^IAM) can be successfully used as permeability classifiers of ampholytes. Moreover, a pragmatic classification into ordinary ampholytes; zwitterions 'certain' (i.e., the zwitterionic species is dominant in the physiological pH range); and zwitterions 'uncertain' (multiple species are present in the physiological pH range) enables to study the permeability of ampholytic compounds in relation to species distribution. Methodology: Potentiometry (pK_a), reversed-phase (RP)-chromatography, tri-layer parallel artificial membrane permeability assays, quantitative structure-property relationships (QSPR) and block relevance (BR) analysis, receiver operating characteristic (ROC) curves. Conclusion: Structures considered as poorly permeable like zwitterions can be integrated in drug discovery programs by applying ad hoc experimental and computational tools.