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Reverse fingerprinting, similarity searching by group fusion and fingerprint bit importance

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Summary

Recent research has shown that using data fusion rules in fingerprint-based similarity searching can improve results over traditional searches. Group fusion scores, which use multiple reference compounds, have in particular been shown to be quite effective in increasing enrichment rates over single reference structure based searches. In this paper, the effectiveness of using data fusion with multiple reference compounds to increase similarity search recall rates was investigated using 44 biological targets and four different 2D fingerprinting systems, including a new 2D typed triangle fingerprinting system introduced here. Scaffold-hopping abilities using data fusion rules were investigated using eight (8) different classes of scaffolds active against cGMP phosphodiesterase isoform 5 (PDE5). An approach to using the reference group for ranking and visualizing important fingerprints bits, or reverse fingerprinting, was presented, and used to score and visualize important pharmacophore features within sample active molecules. Finally, similarity statistics within the reference groups were investigated and compared to recall rates.

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Abbreviations

GpiDAPH:

graph pi-donor-acceptor-polar-hydrophobe fingerprints

TGT:

typed graph triangle fingerprints

PCH:

polar-charged-hydrophobe fingerprints

MACCS:

166 public MACCS keys

n :

group count (# of reference structures)

ROC:

receiver operator characteristic curve

AVE:

average fusion rule

MAX:

maximum fusion rule

vHTS:

virtual high-throughput screening

Ck :

bit coverage in the training group

Tk :

bit importance

wL :

pharmacophore fragment score

fk i :

bit position

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  1. Chemical Computing Group Inc., 1010 Sherbrooke Street West, Suite 910, Montreal, H3A 2R7, Canada

    Chris Williams

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Williams, C. Reverse fingerprinting, similarity searching by group fusion and fingerprint bit importance. Mol Divers 10, 311–332 (2006). https://doi.org/10.1007/s11030-006-9039-z

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