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Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1
The human gamma aminobutyric acid transporter subtype 1 (hGAT1) located in the nerve terminals is known to catalyze the neuronal function by the electrogenic reuptake of γ-aminobutyric acid (GABA) with the co-transport of Na(+) and Cl(−) ions. In the past, there has been a major research drive focus...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587590/ https://www.ncbi.nlm.nih.gov/pubmed/33081136 http://dx.doi.org/10.3390/molecules25204745 |
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author | Zafar, Sadia Jabeen, Ishrat |
author_facet | Zafar, Sadia Jabeen, Ishrat |
author_sort | Zafar, Sadia |
collection | PubMed |
description | The human gamma aminobutyric acid transporter subtype 1 (hGAT1) located in the nerve terminals is known to catalyze the neuronal function by the electrogenic reuptake of γ-aminobutyric acid (GABA) with the co-transport of Na(+) and Cl(−) ions. In the past, there has been a major research drive focused on the dysfunction of hGAT1 in several neurological disorders. Thus, hGAT1 of the GABAergic system has been well established as an attractive target for such diseased conditions. Till date, there are various reports about stereo selectivity of –COOH group of tiagabine, a Food and Drug Administration (FDA)-approved hGAT1-selective antiepileptic drug. However, the effect of the stereochemistry of the protonated –NH group of tiagabine has never been scrutinized. Therefore, in this study, tiagabine has been used to explore the binding hypothesis of different enantiomers of tiagabine. In addition, the impact of axial and equatorial configuration of the–COOH group attached at the meta position of the piperidine ring of tiagabine enantiomers was also investigated. Further, the stability of the finally selected four hGAT1–tiagabine enantiomers namely entries 3, 4, 6, and 9 was evaluated through 100 ns molecular dynamics (MD) simulations for the selection of the best probable tiagabine enantiomer. The results indicate that the protonated –NH group in the R-conformation and the –COOH group of Tiagabine in the equatorial configuration of entry 4 provide maximum strength in terms of interaction within the hGAT1 binding pocket to prevent the change in hGAT1 conformational state, i.e., from open-to-out to open-to-in as compared to other selected tiagabine enantiomers 3, 6, and 9. |
format | Online Article Text |
id | pubmed-7587590 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75875902020-10-29 Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 Zafar, Sadia Jabeen, Ishrat Molecules Article The human gamma aminobutyric acid transporter subtype 1 (hGAT1) located in the nerve terminals is known to catalyze the neuronal function by the electrogenic reuptake of γ-aminobutyric acid (GABA) with the co-transport of Na(+) and Cl(−) ions. In the past, there has been a major research drive focused on the dysfunction of hGAT1 in several neurological disorders. Thus, hGAT1 of the GABAergic system has been well established as an attractive target for such diseased conditions. Till date, there are various reports about stereo selectivity of –COOH group of tiagabine, a Food and Drug Administration (FDA)-approved hGAT1-selective antiepileptic drug. However, the effect of the stereochemistry of the protonated –NH group of tiagabine has never been scrutinized. Therefore, in this study, tiagabine has been used to explore the binding hypothesis of different enantiomers of tiagabine. In addition, the impact of axial and equatorial configuration of the–COOH group attached at the meta position of the piperidine ring of tiagabine enantiomers was also investigated. Further, the stability of the finally selected four hGAT1–tiagabine enantiomers namely entries 3, 4, 6, and 9 was evaluated through 100 ns molecular dynamics (MD) simulations for the selection of the best probable tiagabine enantiomer. The results indicate that the protonated –NH group in the R-conformation and the –COOH group of Tiagabine in the equatorial configuration of entry 4 provide maximum strength in terms of interaction within the hGAT1 binding pocket to prevent the change in hGAT1 conformational state, i.e., from open-to-out to open-to-in as compared to other selected tiagabine enantiomers 3, 6, and 9. MDPI 2020-10-16 /pmc/articles/PMC7587590/ /pubmed/33081136 http://dx.doi.org/10.3390/molecules25204745 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zafar, Sadia Jabeen, Ishrat Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 |
title | Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 |
title_full | Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 |
title_fullStr | Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 |
title_full_unstemmed | Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 |
title_short | Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1 |
title_sort | molecular dynamic simulations to probe stereoselectivity of tiagabine binding with human gat1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587590/ https://www.ncbi.nlm.nih.gov/pubmed/33081136 http://dx.doi.org/10.3390/molecules25204745 |
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