Analog Accessibility Score (AAscore) for Rational Compound Selection.

Various in silico scores have been proposed to objectively assess the characteristics and properties of a compound. However, there is still no score that represents the analog accessibility of a compound. Such a score would be valuable for selecting compounds proposed by virtual screening or for prioritizing hit compounds for the hit-to-lead phase. This study proposes an analog accessibility score (AAscore), where retrosynthesis prediction and forward product prediction models were utilized to generate virtual analogs. The AAscore is defined as the number of unique analogs and virtual synthetic routes. To evaluate the AAscore in terms of the number of actually synthesized analog compounds, analog compounds were prepared by using the compound-core relationship (CCR) method. It was found that the AAscore was little correlated with the number of CCR-based analogs. Furthermore, AAscores were found to be significantly influenced by the number of extracted candidate reactants from a reactant database. A case study targeting compounds active against carbonic anhydrase 2 showed that the AAscore could identify compounds that were synthesized into analogs.