title: In Silico Prediction of Human Sulfotransferase 1E1 Activity Guided by Pharmacophores from Molecular Dynamics Simulations.
abstract: Acting during phase II metabolism, sulfotransferases (SULTs) serve detoxification by transforming a broad spectrum of compounds from pharmaceutical, nutritional, or environmental sources into more easily excretable metabolites. However, SULT activity has also been shown to promote formation of reactive metabolites that may have genotoxic effects. SULT subtype 1E1 (SULT1E1) was identified as a key player in estrogen homeostasis, which is involved in many physiological processes and the pathogenesis of breast and endometrial cancer. The development of an in silico prediction model for SULT1E1 ligands would therefore support the development of metabolically inert drugs and help to assess health risks related to hormonal imbalances. Here, we report on a novel approach to develop a model that enables prediction of substrates and inhibitors of SULT1E1. Molecular dynamics simulations were performed to investigate enzyme flexibility and sample protein conformations. Pharmacophores were developed that served as a cornerstone of the model, and machine learning techniques were applied for prediction refinement. The prediction model was used to screen the DrugBank (a database of experimental and approved drugs): 28% of the predicted hits were reported in literature as ligands of SULT1E1. From the remaining hits, a selection of nine molecules was subjected to biochemical assay validation and experimental results were in accordance with the in silico prediction of SULT1E1 inhibitors and substrates, thus affirming our prediction hypotheses.
authors.affiliation: From the Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2/4, 14195 Berlin.
authors.forename: Christin
authors.initials: C
authors.lastname: Rakers
authors.affiliation: the Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, and the Department of Molecular Biology, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schumacher
authors.affiliation: the Departments of Molecular Toxicology and Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal.
authors.forename: Walter
authors.initials: W
authors.lastname: Meinl
authors.affiliation: Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.affiliation: the Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, and.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: From the Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2/4, 14195 Berlin, gerhard.wolber@fu-berlin.de.
authors.forename: Gerhard
authors.identifier: http://orcid.org/0000-0002-5344-0048
authors.initials: G
authors.lastname: Wolber
mesh_terms: D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D000069550:Machine Learning; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D015203:Reproducibility of Results; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D060388:Support Vector Machine; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D015238:Sulfotransferases; C020122:estrone sulfotransferase
keywords: drug design; drug metabolism; liver metabolism; molecular dynamics; molecular modeling; sulfotransferase