Fingerprint scaling increases the probability of identifying molecules with similar activity in virtual screening calculations

Results of systematic virtual screening calculations using a structural key -type fingerprint are reported for compounds belonging to 14 activity class es added to randomly selected synthetic molecules. For each class, a finger print profile was calculated to monitor the relative occupancy of fingerpri nt bit positions. Consensus bit patterns were determined consisting of all bits that were always set on in compounds belonging to a specific activity class. In virtual screening calculations, scale factors were applied to eac h consensus bit position in fingerprints of query molecules. This technique , called "fingerprint scaling", effectively increases the weight of consens us bit positions in fingerprint comparisons. Although overall prediction ac curacy was satisfactory using unsealed calculations, scaling significantly increased the number of correct predictions but only slightly increased the rate of false positives. These observations suggest that fingerprint scali ng is an attractive approach to increase the probability of identifying mol ecules with similar activity by virtual screening. It requires the availabi lity of a series of related compounds and can be easily applied to any keye d fingerprint representation that associates bit positions with specific mo lecular features.