The robust first-principles prediction of pKa values of organic molecules to within an accuracy of 1 pKa unit or less is an important computational challenge. Various empirical and quantum-mechanical based protocols have been successfully applied to this task in the case of small, simple organic molecules with approximately 20-30 atoms.  However, a more formidable challenge is often presented by many drug-like molecules of interest to industry. Such systems may exhibit multiple pKa-active functional groups, different tautomeric forms, a complex conformational space, and steric or stereochemical effects. Further complications may include the influence of hydrogen or other non-covalent bonding interactions, zwitterionic effects, and reactivity with the solvent.  All of these could potentially contribute to the observed pKa in interrelated ways, easily shifting the final value by several log units. <br/> <br/>In this talk, we present our Jaguar macro-pKa predictor, which is a DFT-based workflow incorporating molecular dynamics and data-driven empirical corrections. The latest version of our protocol aims to address many of the challenges summarized above in an automated fashion.  A complete computational approach to the prediction of these macro-pKa values, avoiding any user input beyond the input structure, requires not only new scientific insights, but also the implementation of a sophisticated computational platform. We present a discussion of both the scientific and technical challenge and how it became feasible to run such a workflow in practice involving the consideration of potentially hundreds of tautomers, conformers, stereochemical species and individual micro-pKa calculations.  We give examples of the success of our tool when applied to challenging molecules that cannot be described accurately with simpler approaches, especially those that are rooted in a 2D representation of the underlying molecules.

Engineering a DFT-based macro-pKa predictor for drug-like molecules, including tautomeric, conformational and stereochemical effects

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.