{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:45:33Z","timestamp":1760240733998,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,14]],"date-time":"2019-09-14T00:00:00Z","timestamp":1568419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2017\/27\/B\/NZ7\/01767"],"award-info":[{"award-number":["2017\/27\/B\/NZ7\/01767"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In order to search for novel antipsychotics acting through the D2 receptor, it is necessary to know the structure\u2013activity relationships for dopamine D2 receptor antagonists. In this context, we constructed the universal three-dimensional quantitative structure\u2013activity relationship (3D- QSAR) model for competitive dopamine D2 receptor antagonists. We took 176 compounds from chemically different groups characterized by the half maximal inhibitory concentration (IC50)from the CHEMBL database and docked them to the X-ray structure of the human D2 receptor in the inactive state. Selected docking poses were applied for Comparative Molecular Field Analysis (CoMFA) alignment. The obtained CoMFA model is characterized by a cross-validated coefficient Q2 of 0.76 with an optimal component of 5, R2 of 0.92, and an F value of 338.9. The steric and electrostatic field contributions are 67.4% and 32.6%, respectively. The statistics obtained prove that the CoMFA model is significant. Next, the IC50 of the 16 compounds from the test set was predicted with R2 of 0.95. Finally, a progressive scrambling test was carried out for additional validation. The CoMFA fields were mapped onto the dopamine D2 receptor binding site, which enabled a discussion of the structure\u2013activity relationship based on ligand\u2013receptor interactions. In particular, it was found that one of the desired steric interactions covers the area of a putative common allosteric pocket suggested for some other G protein-coupled receptors (GPCRs), which would suggest that some of the known dopamine receptor antagonists are bitopic in their essence. The CoMFA model can be applied to predict the potential activity of novel dopamine D2 receptor antagonists.<\/jats:p>","DOI":"10.3390\/ijms20184555","type":"journal-article","created":{"date-parts":[[2019,9,16]],"date-time":"2019-09-16T03:17:57Z","timestamp":1568603877000},"page":"4555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Universal 3D QSAR Model for Dopamine D2 Receptor Antagonists"],"prefix":"10.3390","volume":"20","author":[{"given":"Agata","family":"Zi\u0119ba","sequence":"first","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodzki St, PL-20059 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justyna","family":"\u017buk","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodzki St, PL-20059 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-376X","authenticated-orcid":false,"given":"Damian","family":"Bartuzi","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodzki St, PL-20059 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dariusz","family":"Matosiuk","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodzki St, PL-20059 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4196-4204","authenticated-orcid":false,"given":"Antti","family":"Poso","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland"},{"name":"Department. of Internal Medicine VIII, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Strasse 14, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-9623","authenticated-orcid":false,"given":"Agnieszka A.","family":"Kaczor","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodzki St, PL-20059 Lublin, Poland"},{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"St\u0119pnicki, P., Kondej, M., and Kaczor, A.A. (2018). Current concepts and treatments of schizophrenia. Molecules, 23.","DOI":"10.3390\/molecules23082087"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yang, A.C., and Tsai, S.-J. (2017). New targets for schizophrenia treatment beyond the dopamine hypothesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081689"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nature25758","article-title":"Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone","volume":"555","author":"Wang","year":"2018","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1021\/ci400004e","article-title":"X-ray crystallographic structures as a source of ligand alignment in 3D-QSAR","volume":"53","year":"2013","journal-title":"J. Chem. Inf. Model."},{"key":"ref_5","first-page":"647","article-title":"Strategies and recent technologies in drug discovery","volume":"50","author":"Kubinyi","year":"1995","journal-title":"Pharmazie"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5959","DOI":"10.1021\/ja00226a005","article-title":"Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins","volume":"110","author":"Cramer","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s10822-008-9227-2","article-title":"Using a staged multi-objective optimization approach to find selective pharmacophore models","volume":"23","author":"Clark","year":"2009","journal-title":"J. Comput. Aided Msol. Des."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1007\/s00044-018-2137-5","article-title":"Comparative molecular field analysis and molecular dynamics studies of the dopamine D2 receptor antagonists without a protonatable nitrogen atom","volume":"27","author":"Kaczor","year":"2018","journal-title":"Med. Chem. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/s00894-015-2789-8","article-title":"Comparative molecular field analysis and molecular dynamics studies of \u03b1\/\u03b2 hydrolase domain containing 6 (ABHD6) inhibitors","volume":"21","author":"Kaczor","year":"2015","journal-title":"J. Mol. Model."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4856","DOI":"10.1016\/j.ejmech.2010.07.056","article-title":"QSAR prediction of D2 receptor antagonistic activity of 6-methoxy benzamides","volume":"45","author":"Fatemi","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1021\/ci1002747","article-title":"Subtype selectivity of dopamine receptor ligands: Insights from structure and ligand-based methods","volume":"50","author":"Wang","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1021\/cn300142q","article-title":"Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds","volume":"3","author":"Luedtke","year":"2012","journal-title":"ACS Chem. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"D945","DOI":"10.1093\/nar\/gkw1074","article-title":"The ChEMBL database in 2017","volume":"45","author":"Gaulton","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.ejmech.2019.07.050","article-title":"Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs","volume":"180","author":"Kondej","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1043-9471(05)80049-7","article-title":"Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors","volume":"25","author":"Ballesteros","year":"1995","journal-title":"Methods Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/cmdc.201500599","article-title":"Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics","volume":"11","author":"Kaczor","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neuint.2016.03.003","article-title":"In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic","volume":"96","author":"Kaczor","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kondej, M., Bartyzel, A., Pitucha, M., Wr\u00f3bel, T.M., Silva, A.G., Matosiuk, D., Castro, M., and Kaczor, A.A. (2018). Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D\u2082 Receptor Ligand. Molecules, 23.","DOI":"10.3390\/molecules23092249"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8042","DOI":"10.1016\/j.bmc.2008.07.070","article-title":"Quantitative structure-activity relationship studies on nitrofuranyl anti-tubercular agents","volume":"16","author":"Hevener","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s10822-004-4077-z","article-title":"Statistical variation in progressive scrambling","volume":"18","author":"Clark","year":"2004","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10112","DOI":"10.1002\/anie.201302244","article-title":"The role of water and sodium ions in the activation of the \u03bc-opioid receptor","volume":"52","author":"Yuan","year":"2013","journal-title":"Angew. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1021\/acs.jcim.5b00705","article-title":"Interplay between Two Allosteric Sites and Their Influence on Agonist Binding in Human \u03bc Opioid Receptor","volume":"56","author":"Bartuzi","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1124\/mol.117.109561","article-title":"Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors","volume":"93","author":"Livingston","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neuropharm.2017.03.007","article-title":"Residues W320 and Y328 within the binding site of the \u03bc-opioid receptor influence opiate ligand bias","volume":"118","author":"Hothersall","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1038\/ncomms2028","article-title":"The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling","volume":"3","author":"Bock","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_26","unstructured":"(2018). Schr\u00f6dinger Release 2018-2: LigPrep, Schr\u00f6dinger, LLC."},{"key":"ref_27","unstructured":"(2018). Schr\u00f6dinger Release 2018-2: Epik, Schr\u00f6dinger, LLC."},{"key":"ref_28","unstructured":"(2018). Schr\u00f6dinger Release 2018-2: Glide, Schr\u00f6dinger, LLC."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:20:03Z","timestamp":1760188803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,14]]},"references-count":28,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijms20184555"],"URL":"https:\/\/doi.org\/10.3390\/ijms20184555","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2019,9,14]]}}}