Ring-chain tautomers are characterized by a transition between cyclic and acyclic protonation forms. Such tautomers, commonly found in sugars, fluorescein dyes, and even some drugs (warfarin) have been difficult to generate (or enumerate) with computational algorithms due to the non-locality of the associated proton migration. Available computational tools designed to handle tautomerization effects often ignore ring-chain tautomers. Previous attempts at generating ring-chain tautomers utilized hard-coded rules based on atom types and connectivity patterns. Rules-based approaches will fail to generate certain tautomers if the rules for these specific tautomers are not preliminarily encoded. In this work we propose a novel approach that uses physical atomic descriptors as opposed to rules. This is another application of our novel cheminformatics technique which sets correspondence between local atomic environments using a 3D local atomic descriptor rather than SMARTS patterns. Our technique uses only geometric and quantum-chemical input information and avoids problems with mesomeric (resonance) structures that are present in SMARTS patterns. We show that our algorithm can rapidly and correctly generate both closed (ring) and open (chain) tautomers for a variety of organic structure types. Application of our algorithm to drug design and prediction of physical properties such as pKa will be discussed.

Generation of ring-chain tautomers without rules

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

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