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Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders

Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signa...

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Detalles Bibliográficos
Autores principales: Ademuwagun, Ibitayo Abigail, Oduselu, Gbolahan Oladipupo, Rotimi, Solomon Oladapo, Adebiyi, Ezekiel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989394/
https://www.ncbi.nlm.nih.gov/pubmed/36895324
http://dx.doi.org/10.1177/11779322231158254
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author Ademuwagun, Ibitayo Abigail
Oduselu, Gbolahan Oladipupo
Rotimi, Solomon Oladapo
Adebiyi, Ezekiel
author_facet Ademuwagun, Ibitayo Abigail
Oduselu, Gbolahan Oladipupo
Rotimi, Solomon Oladapo
Adebiyi, Ezekiel
author_sort Ademuwagun, Ibitayo Abigail
collection PubMed
description Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.
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spelling pubmed-99893942023-03-08 Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders Ademuwagun, Ibitayo Abigail Oduselu, Gbolahan Oladipupo Rotimi, Solomon Oladapo Adebiyi, Ezekiel Bioinform Biol Insights Original Research Article Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management. SAGE Publications 2023-03-02 /pmc/articles/PMC9989394/ /pubmed/36895324 http://dx.doi.org/10.1177/11779322231158254 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Research Article
Ademuwagun, Ibitayo Abigail
Oduselu, Gbolahan Oladipupo
Rotimi, Solomon Oladapo
Adebiyi, Ezekiel
Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders
title Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders
title_full Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders
title_fullStr Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders
title_full_unstemmed Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders
title_short Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders
title_sort pharmacophore-aided virtual screening and molecular dynamics simulation identifies trkb agonists for treatment of cdkl5-deficiency disorders
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989394/
https://www.ncbi.nlm.nih.gov/pubmed/36895324
http://dx.doi.org/10.1177/11779322231158254
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