Widespread Misinterpretation of pKa Terminology for Zwitterionic Compounds and Its Consequences.

Abstract

The acid dissociation constant (pK_a), which quantifies the propensity for a solute to donate a proton to its solvent, is crucial for drug design and synthesis, environmental fate studies, chemical manufacturing, and many other fields. Unfortunately, the terminology used for describing acid-base phenomena is sometimes inconsistent, causing large potential for misinterpretation. In this work, we examine a systematic confusion underlying the definition of "acidic" and "basic" pK_a values for zwitterionic compounds. Due to this confusion, some pK_a data are misrepresented in data repositories, including the widely used and highly trusted ChEMBL database. Such datasets are frequently used to supply training data for pK_a prediction models, and hence, confusion and errors in the data make the model performance worse. Herein, we discuss the intricacies of this issue. We make suggestions for describing acid-base phenomena, training pK_a prediction models, and stewarding pK_a datasets, given the high potential for confusion and potentially high impact in downstream applications.