title: Screening of synthetic and natural product databases: Identification of novel androgens and antiandrogens.
abstract: The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors α and β, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds.
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bobach
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tennstedt
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Palberg
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Denkert
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
authors.affiliation: Institute for Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: de Meijere
authors.affiliation: Institute of Medicinal Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle/Saale, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.affiliation: Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany. Electronic address: wessjohann@ipb-halle.de.
authors.forename: Ludger A
authors.initials: LA
authors.lastname: Wessjohann
mesh_terms: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D001688:Biological Products; D008024:Ligands; D011944:Receptors, Androgen
keywords: Androgen receptor; LNCaP cells; PC-3 cells; Proliferation assay; Steroid receptor ligand displacement assay; Virtual screening