Small-Molecule Binders of Prokineticin Receptors Figure 2. SAR analysis of small-molecule PKR antagonists identifies activity-determining chemical groups. The four variable positions in the scaffold – A1, D, L2, and Q, were compared in a dataset composed of 56 active compounds (IC50,0.05 mM) and 51 inactive compounds (IC50.1 mM) to determine the required chemical features at each position that elicit activity (a representative set is shown). These features are indicated in dashed boxes for each position. HB - hydrogen bond. doi:10.1371/journal.pone.0027990.g002 Figure 3. Ligand-based pharmacophore models recapture the known binders. (A) ligand-based four-feature pharmacophores used for virtual screening, with mapping of a known active small-molecule antagonist used for constructing the pharmacophores. The pharmacophores are represented as tolerance spheres with directional vectors where applicable. Green spheres represent hydrogen bond acceptors, red - positive ionizable, light blue – hydrophobic, and orange - aromatic ring. (B) ROC curve demonstrating the enrichment achieved following ligand-based pharmacophore mapping of 56 known active PKR antagonists and 5909 random molecules obtained from the ZINC database. Known actives are significantly enriched by both pharmacophore hypotheses. doi:10.1371/journal.pone.0027990.g003 PLoS ONE | www.plosone.org 6 November 2011 | Volume 6 | Issue 11 | e27990