Pharmacophore alignment search tool: Influence of canonical atom labeling on similarity searching

Previously, (Hähnke et al., J Comput Chem 2009, 30, 761) we presented the Pharmacophore Alignment Search Tool (PhAST), a ligand-based virtual screening technique representing molecules as strings coding pharmacophoric features and comparing them by global pairwise sequence alignment. To guarantee unambiguity during the reduction of two-dimensional molecular graphs to one-dimensional strings, PhAST employs a graph canonization step. Here, we present the results of the comparison of 11 different algorithms for graph canonization with respect to their impact on virtual screening. Retrospective screenings of a drug-like data set were evaluated using the BEDROC metric, which yielded averaged values between 0.4 and 0.14 for the best-performing and worst-performing canonization technique. We compared five scoring schemes for the alignments and found preferred combinations of canonization algorithms and scoring functions. Finally, we introduce a performance index that helps prioritize canonization approaches without the need for extensive retrospective evaluation.