Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies

Alzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide oth...

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Autores: Castro-Álvarez, Alejandro, Chávez-Angel, Emigdio, Nelson, Ronald
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/266181
Acesso em linha:http://hdl.handle.net/10261/266181
Access Level:Acceso aberto
Palavra-chave:Alzheimer's disease
5-HT4
Partial agonist
3D-QSAR
Force and gaussian fields
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spelling Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studiesCastro-Álvarez, AlejandroChávez-Angel, EmigdioNelson, RonaldAlzheimer's disease5-HT4Partial agonist3D-QSARForce and gaussian fieldsAlzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures’ field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R training = 0.821, and for the test set R test = 0.667, while for Gaussian-field QSAR the training and the test were R training = 0.898 and R test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of QLOO = 0.804 and QLOO = 0.886 for force-and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT partial agonists with potential biological activity (pEC 8.209– 9.417 for force-field QSAR and 9.111–9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT partial agonists.A.C.-A. and R.N. would like to acknowledge the FONDECYT program. Ronald Nelson would like to acknowledge the Postdoctoral FONDECYT Grant. ICN2 is supported by the Severo Ochoa program, the Spanish Research Agency (AEI, grant no. SEV-2017-0706), and the CERCA Programme/Generalitat de Catalunya. E.C.-Á. acknowledges support from Spanish MICINN project SIP (PGC2018-101743-B-I00).Multidisciplinary Digital Publishing InstituteAgencia Estatal de Investigación (España)Generalitat de CatalunyaMinisterio de Ciencia, Innovación y Universidades (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/266181reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-101743-B-I00http://doi.org/10.3390/ijms22073602Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2661812026-05-22T06:33:51Z
dc.title.none.fl_str_mv Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
title Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
spellingShingle Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
Castro-Álvarez, Alejandro
Alzheimer's disease
5-HT4
Partial agonist
3D-QSAR
Force and gaussian fields
title_short Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
title_full Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
title_fullStr Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
title_full_unstemmed Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
title_sort Understanding the molecular basis of 5-ht4 receptor partial agonists through 3d-qsar studies
dc.creator.none.fl_str_mv Castro-Álvarez, Alejandro
Chávez-Angel, Emigdio
Nelson, Ronald
author Castro-Álvarez, Alejandro
author_facet Castro-Álvarez, Alejandro
Chávez-Angel, Emigdio
Nelson, Ronald
author_role author
author2 Chávez-Angel, Emigdio
Nelson, Ronald
author2_role author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Generalitat de Catalunya
Ministerio de Ciencia, Innovación y Universidades (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Alzheimer's disease
5-HT4
Partial agonist
3D-QSAR
Force and gaussian fields
topic Alzheimer's disease
5-HT4
Partial agonist
3D-QSAR
Force and gaussian fields
description Alzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures’ field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R training = 0.821, and for the test set R test = 0.667, while for Gaussian-field QSAR the training and the test were R training = 0.898 and R test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of QLOO = 0.804 and QLOO = 0.886 for force-and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT partial agonists with potential biological activity (pEC 8.209– 9.417 for force-field QSAR and 9.111–9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT partial agonists.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/266181
url http://hdl.handle.net/10261/266181
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-101743-B-I00
http://doi.org/10.3390/ijms22073602
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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