Electron density fingerprints (EDprints): Virtual screening using assembled information of electron density

TY - JOUR

T1 - Electron density fingerprints (EDprints)

T2 - Virtual screening using assembled information of electron density

AU - Kooistra, Albert J.

AU - Binsl, Thomas W.

AU - Van Beek, Johannes H.G.M.

AU - De Graaf, Chris

AU - Heringa, Jaap

PY - 2010/10/25

Y1 - 2010/10/25

N2 - We have designed a method to encode properties related to the electron densities of molecules (calculated 1H and 13C NMR shifts and atomic partial charges) in molecular fingerprints (EDprints). EDprints was evaluated in terms of their retrospective virtual screening accuracy against the Directory of Useful Decoys (DUD) and compared to the established ligand-based similarity search methods MOLPRINT 2D and FCFP-4. Although there are no significant differences in the overall virtual screening accuracies of the three methods, specific examples highlight interesting differences between the new EDprints fingerprint method and the atom-centered circular fingerprint methods of MOLPRINT 2D and FCFP-4. On one hand, EDprints similarity searches can be biased by the molecular protonation state, especially when reference ligands contain multiple ionizable groups. On the other hand, EDprints models are more robust toward subtle rearrangements of chemical groups and more suitable for screening against reference molecules with fused ring systems than MOLPRINT 2D and FCFP-4. EDprints is furthermore the fastest method under investigation in comparing fingerprints (average 56-233-fold increase in speed), which makes it highly suitable for all-against-all similarity searches and for repetitive virtual screening against large chemical databases of millions of compounds.

AB - We have designed a method to encode properties related to the electron densities of molecules (calculated 1H and 13C NMR shifts and atomic partial charges) in molecular fingerprints (EDprints). EDprints was evaluated in terms of their retrospective virtual screening accuracy against the Directory of Useful Decoys (DUD) and compared to the established ligand-based similarity search methods MOLPRINT 2D and FCFP-4. Although there are no significant differences in the overall virtual screening accuracies of the three methods, specific examples highlight interesting differences between the new EDprints fingerprint method and the atom-centered circular fingerprint methods of MOLPRINT 2D and FCFP-4. On one hand, EDprints similarity searches can be biased by the molecular protonation state, especially when reference ligands contain multiple ionizable groups. On the other hand, EDprints models are more robust toward subtle rearrangements of chemical groups and more suitable for screening against reference molecules with fused ring systems than MOLPRINT 2D and FCFP-4. EDprints is furthermore the fastest method under investigation in comparing fingerprints (average 56-233-fold increase in speed), which makes it highly suitable for all-against-all similarity searches and for repetitive virtual screening against large chemical databases of millions of compounds.

UR - http://www.scopus.com/inward/record.url?scp=77958613815&partnerID=8YFLogxK

U2 - 10.1021/ci1002608

DO - 10.1021/ci1002608

M3 - Journal article

C2 - 20839826

AN - SCOPUS:77958613815

SN - 1549-9596

VL - 50

SP - 1772

EP - 1780

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

IS - 10

ER -