Apparent asymmetry in fingerprint similarity searching is a direct consequence of differences in bit densities and molecular size.

Recently, systematic similarity calculations using Tversky coefficients have suggested that putting higher weight on bit settings of active reference molecules (templates) than database compounds increases hit rates in similarity searching using 2D fingerprints. These findings have been interpreted as evidence for "asymmetry" in chemical similarity searching. We have thoroughly analyzed this phenomenon and demonstrate that apparent asymmetry in similarity search calculations is a direct consequence of differences in fingerprint bit densities, which often correlate with differences in molecular size. Accordingly, a size-independent fingerprint with constant bit density does not produce asymmetrical search results. For Tversky similarity calculations, differences in fingerprint bit densities between active and inactive compounds determine which weighting factors produce high hit rates.