title: Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics.
abstract: Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction.
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division for Medical Analytics, Medical University of Lublin, 4A Chodźki St., 20059, Lublin, Poland. agnieszka.kaczor@umlub.pl.|School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70211, Kuopio, Finland. agnieszka.kaczor@umlub.pl.
authors.forename: Agnieszka A
authors.identifier: http://orcid.org/0000-0001-8679-9623
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, 15782, Santiago de Compostela, Spain.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, 15782, Santiago de Compostela, Spain.
authors.forename: María I
authors.initials: MI
authors.lastname: Loza
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolb
authors.affiliation: Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, 15782, Santiago de Compostela, Spain.
authors.forename: Marián
authors.initials: M
authors.lastname: Castro
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70211, Kuopio, Finland.|University Hospital Tübingen, Department of Internal Medicine I, Division of Translational Gastrointestinal Oncology, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D008024:Ligands; D017448:Receptors, Dopamine D2
keywords: antipsychotics; dopamine D2 receptor; dopamine D2 receptor antagonists; structure-based virtual screening