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

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.

Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

“…1A. LBVS was performed using pharmacophore and shape similarity scoring functions recently developed in our laboratory [20][21][22][23]. A total 140 compounds were purchased as 1 mg solid sample from Princeton Biomolecular Research (Monmouth Junction, NJ, USA) and conditioned as 10 mM stocks in DMSO.…”

Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand‐Based Virtual Screening Method

“…[10] LOS was computed separately for hydrophobic atoms,h ydrogen bond donor and acceptor atoms which were previously found to be useful atom categories for pharmacophore fingerprint design. [11] Only the lowest energy conformer generated by CORINA [12] was used as 3D-model of each molecule because sampling multiple conformers would increase computational costs by at least 100-fold and has been shown to not yield clear performance benefits in related 3D LBVS methods. [13] Thec ombined score was maximized by alignment and iterative translation and rotation of query relative to seed molecule along their principal molecular axes ( Figure 1A-C;S upporting Information, Figure S2).…”

Isolation of Compounds from <i>Sargassum wightii </i> by GCMS and the Molecular Docking against Anti-Inflammatory Marker COX2

“…The ligands are freely available and are able to download from the web databases like ZINC [18] and Pubchem [19,20], and they provide the knowledge about their biological activities. The small ligand molecule if unable to download, then it can be sketched using tools like Chemdraw or Chemsketch.…”