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Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints.

Awale M, Jin X, Reymond JL - J Cheminform (2015)

Bottom Line: We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry.Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances. 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases.Graphical abstractAtom pair fingerprints based on through-space distances (3DAPfp) provide better shape encoding than atom pair fingerprints based on topological distances (APfp) as measured by the recovery of ROCS shape analogs by fp similarity.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.

ABSTRACT

Background: Tools to explore large compound databases in search for analogs of query molecules provide a strategically important support in drug discovery to help identify available analogs of any given reference or hit compound by ligand based virtual screening (LBVS). We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry. Here we investigated related 3D-atom pair fingerprints to enable rapid stereoselective searches in the ZINC database (23.2 million 3D structures).

Results: Molecular fingerprints counting atom pairs at increasing through-space distance intervals were designed using either all atoms (16-bit 3DAPfp) or different atom categories (80-bit 3DXfp). These 3D-fingerprints retrieved molecular shape and pharmacophore analogs (defined by OpenEye ROCS scoring functions) of 110,000 compounds from the Cambridge Structural Database with equal or better accuracy than the 2D-fingerprints APfp and Xfp, and showed comparable performance in recovering actives from decoys in the DUD database. LBVS by 3DXfp or 3DAPfp similarity was stereoselective and gave very different analogs when starting from different diastereomers of the same chiral drug. Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances.

Conclusions: 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases. Web-browsers for searching ZINC by 3DAPfp and 3DXfp similarity are accessible at www.gdb.unibe.ch and should provide useful assistance to drug discovery projects. Graphical abstractAtom pair fingerprints based on through-space distances (3DAPfp) provide better shape encoding than atom pair fingerprints based on topological distances (APfp) as measured by the recovery of ROCS shape analogs by fp similarity.

No MeSH data available.


Related in: MedlinePlus

Recovery of ROCS analogs in CSD using 3D and 2D fingerprints. A. AUC values with 3DAPfp or 3DXfp (y-axis) vs. AUC values with APfp or Xfp (x-axis). The scatter plots are coloured according to compounds/pixel: Red = ≥25, Yellow = 19, Green = 12, Cyan = 6 and Blue = 1. B. Examples for which recovery of ROCS Shape Tanimoto analogs is better with 3DAPfp than with APfp. C. Examples for which recovery is better with APfp than with 3DAPfp.
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Fig3: Recovery of ROCS analogs in CSD using 3D and 2D fingerprints. A. AUC values with 3DAPfp or 3DXfp (y-axis) vs. AUC values with APfp or Xfp (x-axis). The scatter plots are coloured according to compounds/pixel: Red = ≥25, Yellow = 19, Green = 12, Cyan = 6 and Blue = 1. B. Examples for which recovery of ROCS Shape Tanimoto analogs is better with 3DAPfp than with APfp. C. Examples for which recovery is better with APfp than with 3DAPfp.

Mentions: Analysis of the AUC values for recovery of ROCS analogs of individual CSD compounds using 3D vs. the corresponding 2D fingerprint further illustrated the generally superior performance of 3DAPfp vs. APfp, and the comparable performance of 3DXfp and Xfp (Figure 3A). For cases where the AUC values were higher for 3DAPfp than for APfp such as compounds 1–4, a folded conformation was observed in the crystal structure. In such folded structures topological distances overestimate the actual through-space distances separating atom pairs, explaining the lower performance of the 2D-fingerprint. The folded conformation was caused by intramolecular H-bonds in the case of 1–3 and a π-stack effect in compound 4 (Figure 3B). On the other hand, the 2D-fingerprint APfp performed better than 3DAPfp in a significant number of cases, in particular for molecules with a large number of sulfur and halogen atoms as for 5–8 (Figure 3C). This effect is difficult to rationalize because it occurs independent of molecular shape in both planar (e.g. 6 and 7) and spherical (e.g. 5 and 8) molecules.Figure 3


Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints.

Awale M, Jin X, Reymond JL - J Cheminform (2015)

Recovery of ROCS analogs in CSD using 3D and 2D fingerprints. A. AUC values with 3DAPfp or 3DXfp (y-axis) vs. AUC values with APfp or Xfp (x-axis). The scatter plots are coloured according to compounds/pixel: Red = ≥25, Yellow = 19, Green = 12, Cyan = 6 and Blue = 1. B. Examples for which recovery of ROCS Shape Tanimoto analogs is better with 3DAPfp than with APfp. C. Examples for which recovery is better with APfp than with 3DAPfp.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4352573&req=5

Fig3: Recovery of ROCS analogs in CSD using 3D and 2D fingerprints. A. AUC values with 3DAPfp or 3DXfp (y-axis) vs. AUC values with APfp or Xfp (x-axis). The scatter plots are coloured according to compounds/pixel: Red = ≥25, Yellow = 19, Green = 12, Cyan = 6 and Blue = 1. B. Examples for which recovery of ROCS Shape Tanimoto analogs is better with 3DAPfp than with APfp. C. Examples for which recovery is better with APfp than with 3DAPfp.
Mentions: Analysis of the AUC values for recovery of ROCS analogs of individual CSD compounds using 3D vs. the corresponding 2D fingerprint further illustrated the generally superior performance of 3DAPfp vs. APfp, and the comparable performance of 3DXfp and Xfp (Figure 3A). For cases where the AUC values were higher for 3DAPfp than for APfp such as compounds 1–4, a folded conformation was observed in the crystal structure. In such folded structures topological distances overestimate the actual through-space distances separating atom pairs, explaining the lower performance of the 2D-fingerprint. The folded conformation was caused by intramolecular H-bonds in the case of 1–3 and a π-stack effect in compound 4 (Figure 3B). On the other hand, the 2D-fingerprint APfp performed better than 3DAPfp in a significant number of cases, in particular for molecules with a large number of sulfur and halogen atoms as for 5–8 (Figure 3C). This effect is difficult to rationalize because it occurs independent of molecular shape in both planar (e.g. 6 and 7) and spherical (e.g. 5 and 8) molecules.Figure 3

Bottom Line: We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry.Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances. 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases.Graphical abstractAtom pair fingerprints based on through-space distances (3DAPfp) provide better shape encoding than atom pair fingerprints based on topological distances (APfp) as measured by the recovery of ROCS shape analogs by fp similarity.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.

ABSTRACT

Background: Tools to explore large compound databases in search for analogs of query molecules provide a strategically important support in drug discovery to help identify available analogs of any given reference or hit compound by ligand based virtual screening (LBVS). We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry. Here we investigated related 3D-atom pair fingerprints to enable rapid stereoselective searches in the ZINC database (23.2 million 3D structures).

Results: Molecular fingerprints counting atom pairs at increasing through-space distance intervals were designed using either all atoms (16-bit 3DAPfp) or different atom categories (80-bit 3DXfp). These 3D-fingerprints retrieved molecular shape and pharmacophore analogs (defined by OpenEye ROCS scoring functions) of 110,000 compounds from the Cambridge Structural Database with equal or better accuracy than the 2D-fingerprints APfp and Xfp, and showed comparable performance in recovering actives from decoys in the DUD database. LBVS by 3DXfp or 3DAPfp similarity was stereoselective and gave very different analogs when starting from different diastereomers of the same chiral drug. Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances.

Conclusions: 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases. Web-browsers for searching ZINC by 3DAPfp and 3DXfp similarity are accessible at www.gdb.unibe.ch and should provide useful assistance to drug discovery projects. Graphical abstractAtom pair fingerprints based on through-space distances (3DAPfp) provide better shape encoding than atom pair fingerprints based on topological distances (APfp) as measured by the recovery of ROCS shape analogs by fp similarity.

No MeSH data available.


Related in: MedlinePlus