Systematic assessment of scaffold distances in ChEMBL: prioritization of compound data sets for scaffold hopping analysis in virtual screening

Abstract

The evaluation of the scaffold hopping potential of computational methods is of high relevance for virtual screening. For benchmark calculations, classes of known active compounds are utilized. Ideally, such classes should have a well-defined content of structurally diverse scaffolds. However, in reported benchmark investigations, the choice of activity classes is often difficult to rationalize. To provide a compendium of well-characterized test cases for the assessment of scaffold hopping potential, structural distances between scaffolds were systematically calculated for compound classes available in the ChEMBL database. Nearly seven million scaffold pairs were evaluated. On the basis of the global scaffold distance distribution, a threshold value for large scaffold distances was determined. Compound data sets were ranked based on the proportion of scaffold pairs with large distances they contained, taking additional criteria into account that are relevant for virtual screening. A set of 50 activity classes is provided that represent attractive test cases for scaffold hopping analysis and benchmark calculations.