Pattern-free generation and quantum mechanical scoring of ring-chain tautomers

• Published in: Journal of computer-aided molecular design Vol. 35; no. 4; pp. 417 - 431
• Main Authors: Levine, Daniel S., Watson, Mark A., Jacobson, Leif D., Dickerson, Claire E., Yu, Haoyu S., Bochevarov, Art D.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2021; Springer Nature B.V
• Subjects: Algorithms; Animal Anatomy; Chains; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Density functional theory; Fluorescein; Histology; Isomerism; Molecular Structure; Morphology; Organic chemistry; Organic compounds; Pharmaceutical Preparations - chemistry; Physical Chemistry; Protons; Quantum mechanics; Quantum Theory; Small Molecule Libraries - chemistry; Sugar; Tautomers; Warfarin; Workflow; Quantum mechanical scoring; Pattern-free; Drug design; Ring-chain tautomers; Tautomer generation
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-020-00334-w

In contrast to the computational generation of conventional tautomers, the analogous operation that would produce ring-chain tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pK a prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain tautomers not found using previously published algorithms are successfully located by ours.