Experimental and pKa prediction aspects of tautomerism of drug-like molecules

Molecules that can tautomerize are a challenge to scientists because one must consider the possible tautomers in most tasks involving chemical structures: for example, searching databases, interpreting experimental property measurements, calculating properties, virtual screening, and analyzing structure-bioactivity relationships. The challenge in interpreting property measurements such as pKa values feeds into the general lack of extensive information not only of the relative tautomer stability in water but also the properties of the individual tautomers. This lack of information results in the lack of reliability of computational predictions of tautomer stability or properties. In spite of these problems, pKa calculations are reliable enough that they can be used to filter out high-energy tautomers from databases used for virtual screening. Continuous improvements in both pKa prediction software and theoretical calculations promise further improvements in solving the challenges of tautomers. The expected availability of high-resolution structures of many more tautomer-protein complexes will help guide the selection of the bioactive tautomer when the structure of the complex is not known.