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To do so, pharmacophore models were constructed using the structure of known inhibitors and then they were used in a screening in the ZINCPharmer database to discover hit molecules with the desired structural moieties and drug-likeness properties. Following this, the 50 best ranked molecules were submitted to molecular docking to better understand their atomic interactions and binding poses with the COMT (PDB#6I3C) active site. Additionally, the hits\u2019 ADMET properties were also studied to improve the obtained results and to select the most promising compounds to advance for in-vitro studies. Then, the 10 compounds selected were purchased and studied regarding their in-vitro inhibitory potency on human recombinant membrane-bound COMT (MBCOMT), as well as their cytotoxicity in rat dopaminergic cells (N27) and human dermal fibroblasts (NHDF). Of these, the compound ZIN27985035 displayed the best results: For MBCOMT inhibition an IC50 of 17.6 nM was determined, and low cytotoxicity was observed in both cell lines (61.26 and 40.32 \u03bcM, respectively). Therefore, the promising results obtained, combined with the structure similarity with commercial COMT inhibitors, can allow for the future development of a potential new Parkinson\u2019s disease drug candidate with improved properties.<\/jats:p>","DOI":"10.3390\/ph15010051","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T20:49:38Z","timestamp":1641242978000},"page":"51","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson\u2019s Disease: Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8552-6180","authenticated-orcid":false,"given":"Pedro","family":"Cruz-Vicente","sequence":"first","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"Ana M.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal"}]},{"given":"Oct\u00e1vio","family":"Ferreira","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-8325","authenticated-orcid":false,"given":"Jo\u00e3o A.","family":"Queiroz","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-5108","authenticated-orcid":false,"given":"Samuel","family":"Silvestre","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"},{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Laborat\u00f3rio de F\u00e1rmaco-Toxicologia\u2014UBIMedical, Universidade da Beira Interior, 6200-001 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-7576","authenticated-orcid":false,"given":"Lu\u00eds A.","family":"Passarinha","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal"},{"name":"Laborat\u00f3rio de F\u00e1rmaco-Toxicologia\u2014UBIMedical, Universidade da Beira Interior, 6200-001 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1802-8998","authenticated-orcid":false,"given":"Eugenia","family":"Gallardo","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, Universidade da Beira Interior, 6201-001 Covilha, Portugal"},{"name":"Laborat\u00f3rio de F\u00e1rmaco-Toxicologia\u2014UBIMedical, Universidade da Beira Interior, 6200-001 Covilha, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2174\/1570159X14666151120123025","article-title":"Current Pharmaceutical Treatments and Alternative Therapies of Parkinson\u2019s Disease","volume":"14","author":"Dong","year":"2016","journal-title":"Curr. 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