The existence of multiple tautomeric forms of the same molecule is still a pending issue in drug discovery. The generation of the appropriate tautomers of drug-like molecules is important for the success in virtual screening. The vast majority of tautomeric equilibria consist in prototropic tautomerism which only involves proton migration. However, there is another type of tautomerism much less commonly handled by common drug design tools: ring-chain tautomerism, a tautomeric interconversion where the movement of the proton is accompanied by opening or closing of a ring. It occurs, e.g., in many sugars and in some drugs such as warfarin. We have developed and implemented in the chemoinformatics toolkit CACTVS a set of ring-chain transformation rules to predict ring-chain tautomers. We present a comparison between prototropic tautomerism and ring-chain tautomerism in order to evaluate whether opening and closing of a ring typically has a higher energetical barrier than just the movement of a proton.

Analysis of prototropic and ring-chain tautomerism to predict favorable tautomers in drug-like molecules

247th National Meeting (2014)

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