Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease

Detalhes bibliográficos
Autor(a) principal: Cruz-Vicente, Pedro
Data de Publicação: 2021
Outros Autores: Gonçalves, Ana M., Ferreira, Octávio, Queiroz, João A., Silvestre, Samuel, Passarinha, Luís A., Gallardo, Eugénia
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/144313
Resumo: Associate Laboratory Institute for Health and Bioeconomy—i4HB (project LA/P/0140/2020), which are financed by national funds from FCT/MCTES. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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spelling Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s DiseasePharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation StudiesBioinformaticsCatechol-O-methyltransferaseCytotoxicityInhibitorsMolecular dockingParkinson’s diseasePharmacophore modelingMolecular MedicinePharmaceutical ScienceDrug DiscoverySDG 3 - Good Health and Well-beingAssociate Laboratory Institute for Health and Bioeconomy—i4HB (project LA/P/0140/2020), which are financed by national funds from FCT/MCTES. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.A pharmacophore-based virtual screening methodology was used to discover new catecholO-methyltransferase (COMT) inhibitors with interest in Parkinson’s disease therapy. 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’ 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 µM, 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’s disease drug candidate with improved properties.UCIBIO - Applied Molecular Biosciences UnitDQ - Departamento de QuímicaRUNCruz-Vicente, PedroGonçalves, Ana M.Ferreira, OctávioQueiroz, João A.Silvestre, SamuelPassarinha, Luís A.Gallardo, Eugénia2022-09-27T22:34:04Z2021-12-312021-12-31T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article21application/pdfhttp://hdl.handle.net/10362/144313eng1424-8247PURE: 46265329https://doi.org/10.3390/ph15010051info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:23:52Zoai:run.unl.pt:10362/144313Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:51:29.190797Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies
title Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
spellingShingle Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
Cruz-Vicente, Pedro
Bioinformatics
Catechol-O-methyltransferase
Cytotoxicity
Inhibitors
Molecular docking
Parkinson’s disease
Pharmacophore modeling
Molecular Medicine
Pharmaceutical Science
Drug Discovery
SDG 3 - Good Health and Well-being
title_short Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
title_full Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
title_fullStr Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
title_full_unstemmed Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
title_sort Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease
author Cruz-Vicente, Pedro
author_facet Cruz-Vicente, Pedro
Gonçalves, Ana M.
Ferreira, Octávio
Queiroz, João A.
Silvestre, Samuel
Passarinha, Luís A.
Gallardo, Eugénia
author_role author
author2 Gonçalves, Ana M.
Ferreira, Octávio
Queiroz, João A.
Silvestre, Samuel
Passarinha, Luís A.
Gallardo, Eugénia
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv UCIBIO - Applied Molecular Biosciences Unit
DQ - Departamento de Química
RUN
dc.contributor.author.fl_str_mv Cruz-Vicente, Pedro
Gonçalves, Ana M.
Ferreira, Octávio
Queiroz, João A.
Silvestre, Samuel
Passarinha, Luís A.
Gallardo, Eugénia
dc.subject.por.fl_str_mv Bioinformatics
Catechol-O-methyltransferase
Cytotoxicity
Inhibitors
Molecular docking
Parkinson’s disease
Pharmacophore modeling
Molecular Medicine
Pharmaceutical Science
Drug Discovery
SDG 3 - Good Health and Well-being
topic Bioinformatics
Catechol-O-methyltransferase
Cytotoxicity
Inhibitors
Molecular docking
Parkinson’s disease
Pharmacophore modeling
Molecular Medicine
Pharmaceutical Science
Drug Discovery
SDG 3 - Good Health and Well-being
description Associate Laboratory Institute for Health and Bioeconomy—i4HB (project LA/P/0140/2020), which are financed by national funds from FCT/MCTES. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
publishDate 2021
dc.date.none.fl_str_mv 2021-12-31
2021-12-31T00:00:00Z
2022-09-27T22:34:04Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/144313
url http://hdl.handle.net/10362/144313
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1424-8247
PURE: 46265329
https://doi.org/10.3390/ph15010051
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 21
application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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