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 provid...

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Autores: Castro-Alvarez, Alejandro|||0000-0001-8360-8027, Chávez Ángel, Emigdio|||0000-0002-9783-0806, Nelson, Ronald|||0000-0001-7449-6334
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:241015
Acceso en línea:https://ddd.uab.cat/record/241015
https://dx.doi.org/urn:doi:10.3390/ijms22073602
Access Level:acceso abierto
Palabra clave: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-Alvarez, Alejandro|||0000-0001-8360-8027Chávez Ángel, Emigdio|||0000-0002-9783-0806Nelson, Ronald|||0000-0001-7449-6334Alzheimer'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. 22021-01-0120212021-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/241015https://dx.doi.org/urn:doi:10.3390/ijms22073602reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PGC2018-101743-B-I00Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SEV-2017-0706open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2410152026-06-06T12:50:31Z
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-Alvarez, Alejandro|||0000-0001-8360-8027
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-Alvarez, Alejandro|||0000-0001-8360-8027
Chávez Ángel, Emigdio|||0000-0002-9783-0806
Nelson, Ronald|||0000-0001-7449-6334
author Castro-Alvarez, Alejandro|||0000-0001-8360-8027
author_facet Castro-Alvarez, Alejandro|||0000-0001-8360-8027
Chávez Ángel, Emigdio|||0000-0002-9783-0806
Nelson, Ronald|||0000-0001-7449-6334
author_role author
author2 Chávez Ángel, Emigdio|||0000-0002-9783-0806
Nelson, Ronald|||0000-0001-7449-6334
author2_role author
author
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 2
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/241015
https://dx.doi.org/urn:doi:10.3390/ijms22073602
url https://ddd.uab.cat/record/241015
https://dx.doi.org/urn:doi:10.3390/ijms22073602
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PGC2018-101743-B-I00
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SEV-2017-0706
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
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repository.mail.fl_str_mv
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