Tautomerism in large databases

Abstract

We have used the Chemical Structure DataBase (CSDB) of the NCI CADD Group, an aggregated collection of over 150 small-molecule databases totaling 103.5 million structure records, to conduct tautomerism analyses on one of the largest currently existing sets of real (i.e. not computer-generated) compounds. This analysis was carried out using calculable chemical structure identifiers developed by the NCI CADD Group, based on hash codes available in the chemoinformatics toolkit CACTVS and a newly developed scoring scheme to define a canonical tautomer for any encountered structure. CACTVS’s tautomerism definition, a set of 21 transform rules expressed in SMIRKS line notation, was used, which takes a comprehensive stance as to the possible types of tautomeric interconversion included. Tautomerism was found to be possible for more than 2/3 of the unique structures in the CSDB. A total of 680 million tautomers were calculated from, and including, the original structure records. Tautomerism overlap within the same individual database (i.e. at least one other entry was present that was really only a different tautomeric representation of the same compound) was found at an average rate of 0.3% of the original structure records, with values as high as nearly 2% for some of the databases in CSDB. Projected onto the set of unique structures (by FICuS identifier), this still occurred in about 1.5% of the cases. Tautomeric overlap across all constituent databases in CSDB was found for nearly 10% of the records in the collection.

Principal bicorrelation analysis: Unraveling associations between three data sources

“…These substructure indicators are henceforward referred to as Fingerprint Features (FFs). To address tautomeric conversion, a phenomenon which affects the encoding, compounds were normalized prior to the encoding procedure A c c e p t e d M a n u s c r i p t 5 (Sitzmann et al, 2010). The on-target bioactivity is measured through a dose-response bioassay, resulting in an IC50 value for each compound.…”

Tautomerism in chemical information management systems

“…Structure normalization is performed for any incoming structure set to be registered, or searched by, in CSLS. Each parent structure is then subjected to a hashcode calculation to generate the NCI/CADD identifier [28].…”

“…Currently there are eight identifier variants defined for a structure: FICTS, FICTu, FICuS, FICuu, uuuTS, uuuTu, uuuuS, and uuuuu. Three of them, FICTS, FICuS and uuuuu are searchable for all the structure records in CSLS [28].…”

Experimental and Chemoinformatics Study of Tautomerism in a Database of Commercially Available Screening Samples

“…However, it is possible that such rules for the enumeration of tautomers may be too aggressive and not realistic from an organic chemists’ viewpoint, 17 i.e. they may declare structures to be tautomers which in reality have a high energy barrier for interconversion and can be isolated as different, stable compounds.…”