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Finally, a User-Friendly Way of Computing and Presenting Individual Group Contributions to Polyprotic Ionization of Drugs
EP20461
Poster Title: Finally, a User-Friendly Way of Computing and Presenting Individual Group Contributions to Polyprotic Ionization of Drugs
Submitted on 19 Dec 2013
Author(s): Robert Fraczkiewicz, Marvin Waldman, Robert D. Clark
Affiliations: Simulations Plus
Poster Views: 1,187
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Poster Information
Abstract: An extreme example at the other end of the spectrum is mellitic (benzene hexacarboxylic) acid where the six measured apparent pKa’s range from 1.4 to 7.0 – a span of 5.6 orders of magnitude. Assigning each apparent pKa to a specific group is clearly absurd in this case, since the six carboxylic acid groups are completely equivalent. This potentially confusing situation is clarified by considering microscopic ionization equilibria, yielding a precise thermodynamic picture, replacing the inaccurate and misleading “one group = one pKa” paradigm. We have explored microequilibria theory in detail and have developed novel concepts: the pH-dependent Average Single Proton Acidity (ASPA), and the pH-dependent Average Site Protonation profiles (ASP). The ionization midpoint of the latter– the pK50- is pH-independent and closely related to concepts from the physical chemistry of proteins. We show that the pK50, unlike macroscopic pKa, is a transferable property of an individual ionisable group, illustrating its inherent acidity in the absence of intergroup interactions. For example, we calculate a chemically realistic pK50=3.92 for each carboxyl group in mellitic acid. In the case of monoprotic molecules as well as molecules with well-separated ionization patterns, the pK50’s correspond to macroscopic pKa‘s exactly and approximately, respectively. An added bonus is a direct determination of individual site occupancies from the calculated ASP at any pH of interest, which eliminates the need to deduce these quantities from pKa.Summary: It is tempting to “assign” the macroscopic ionization constants (apparent pKa‘s obtained from titration experiments) of molecules to specific ionizable groups; however, this is strictly appropriate only in the case of monoprotic molecules.Report abuse »
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