title: Identification of estrogen receptor α ligands with virtual screening techniques.
abstract: Utilization of computer-aided molecular discovery methods in virtual screening (VS) is a cost-effective approach to identify novel bioactive small molecules. Unfortunately, no universal VS strategy can guarantee high hit rates for all biological targets, but each target requires distinct, fine-tuned solutions. Here, we have studied in retrospective manner the effectiveness and usefulness of common pharmacophore hypothesis, molecular docking and negative image-based screening as potential VS tools for a widely applied drug discovery target, estrogen receptor α (ERα). The comparison of the methods helps to demonstrate the differences in their ability to identify active molecules. For example, structure-based methods identified an already known active ligand from the widely-used bechmarking decoy molecule set. Although prospective VS against one commercially available database with around 100,000 drug-like molecules did not retrieve many testworthy hits, one novel hit molecule with pIC50 value of 6.6, was identified. Furthermore, our small in-house compound collection of easy-to-synthesize molecules was virtually screened against ERα, yielding to five hit candidates, which were found to be active in vitro having pIC50 values from 5.5 to 6.5.
authors.affiliation: Department of Biological and Environmental Science & Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014, Finland.
authors.forename: Sanna P
authors.initials: SP
authors.lastname: Niinivehmas
authors.affiliation: Department of Biological and Environmental Science & Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014, Finland; School of Pharmacy, Devi Ahilya University, Indore 452001, Madhya Pradesh, India.
authors.forename: Elangovan
authors.initials: E
authors.lastname: Manivannan
authors.affiliation: Department of Biological and Environmental Science & Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Rauhamäki
authors.affiliation: Department of Chemistry & Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014, Finland.
authors.forename: Juhani
authors.initials: J
authors.lastname: Huuskonen
authors.affiliation: Department of Biological and Environmental Science & Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014, Finland. Electronic address: olli.t.pentikainen@jyu.fi.
authors.forename: Olli T
authors.initials: OT
authors.lastname: Pentikäinen
mesh_terms: D019540:Area Under Curve; D003198:Computer Simulation; D055808:Drug Discovery; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D054852:Small Molecule Libraries
keywords: 3D-QSAR; Estrogen receptor alpha; Ligand discovery; Molecular docking; Negative image; Pharmacophore modeling; Virtual screening