Effectiveness of 2D fingerprints for scaffold hopping

Abstract

Background: It has been suggested that similarity searching using 2D fingerprints may not be suitable for scaffold hopping. Methods: This article reports a detailed evaluation of the effectiveness of six common types of 2D fingerprints when they are used for scaffold-hopping similarity searches of the Molecular Design Limited Drug Data Report database, World of Molecular Bioactivity database and Maximum Unbiased Validation database. Results: The results demonstrate that 2D fingerprints can be used for scaffold hopping, with novel scaffolds being identified in nearly every search that was carried out. The degree of enrichment depends on the structural diversity of the actives that are being sought, with the greatest enrichments often being obtained using the extended connectivity fingerprint encoding a circular substructure of diameter four bonds (ECFP4) fingerprint. Conclusion: 2D fingerprints provide a simple and computationally efficient way of identifying novel chemotypes in lead-discovery programs.