ZWITTERIONS IN DRUG DISCOVERY: STUDIES OF THE TAUTOMERIC EQUILIBRIUM WITH IN-SILICO AND EXPERIMENTAL TOOLS

The need for compounds bRo5 which can bear more ionizable centers has recently increased the interest for zwitterions in drug research either as candidates or as their metabolites. Zwitterionic ampholytes share an acidic and a basic group which can be simultaneously ionized. For zwitterionic ampholytes, the relation pKa acidic < pKa basic is true. A zwitterionic ampholyte can exist in solution in four different electrical states, namely, as a cation, as a charged but globally neutral form called a zwitterion, as a neutral form (N), and as an anion (A). [1] Modeling zwitterions is not an easy task since in principle all electrical states should be considered. A first simplification could be obtained when the isoelectric pH range is large enough to cover most of physiological pH range. If so only the neutral and zwitterionic species can be considered. The ratio of concentrations of the two neutral microspecies (zwitterion/neutral) is the constant of tautomeric equilibrium, called KZ. If KZ is known, it is possible to justify if only one or both of the globally neutral forms has to be modeled for drug discovery purposes. In the effort of setting-up a strategy to evaluate KZ, we selected a few model zwitterions and for any of them we applied UV-Vis spectroscopy to measure KZ and DFT methods to predict it. Through this approach we also try to estimate the influence of the environment which has a dramatic impact on KZ.