The accurate simulation of molecular pKa’s is critical for drug discovery as different protonation states may have profoundly different bioavailability and compartmentalization in different cellular or organ environments. An underappreciated aspect of this problem is reversible reactions with water at different pH’s. We present an automated procedure for determining if a molecule reacts with water at various pH's. We show results where quantitative pKa determination requires recognizing that the true speciation in solution involves hydrated intermediates. In addition to predicting correct speciation at various pHs, the method can also be used to determine the stability of a drug candidate to hydrolysis.

Automatic determination of covalent hydration

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.