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Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2

In this study, we investigated the delivery of synthetic neurosteroids into MCF-7 human breast adenocarcinoma cells via Organic Anionic Transporting Polypeptides (OATPs) (pH 7.4 and 5.5) to identify the structural components required for OATP-mediated cellular uptake and to get insight into brain dr...

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Autores principales: Adla, Santosh Kumar, Tonduru, Arun Kumar, Kronenberger, Thales, Kudova, Eva, Poso, Antti, Huttunen, Kristiina M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472597/
https://www.ncbi.nlm.nih.gov/pubmed/34577133
http://dx.doi.org/10.3390/molecules26185662
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author Adla, Santosh Kumar
Tonduru, Arun Kumar
Kronenberger, Thales
Kudova, Eva
Poso, Antti
Huttunen, Kristiina M.
author_facet Adla, Santosh Kumar
Tonduru, Arun Kumar
Kronenberger, Thales
Kudova, Eva
Poso, Antti
Huttunen, Kristiina M.
author_sort Adla, Santosh Kumar
collection PubMed
description In this study, we investigated the delivery of synthetic neurosteroids into MCF-7 human breast adenocarcinoma cells via Organic Anionic Transporting Polypeptides (OATPs) (pH 7.4 and 5.5) to identify the structural components required for OATP-mediated cellular uptake and to get insight into brain drug delivery. Then, we identified structure-uptake relationships using in-house developed OATP1A2 homology model to predict binding sites and modes for the ligands. These binding modes were studied by molecular dynamics simulations to rationalize the experimental results. Our results show that carboxylic acid needs to be at least at 3 carbon-carbon bonds distance from amide bond at the C-3 position of the androstane skeleton and have an amino group to avoid efflux transport. Replacement of hydroxyl group at C-3 with any of the 3, 4, and 5-carbon chained terminal carboxylic groups improved the affinity. We attribute this to polar interactions between carboxylic acid and side-chains of Lys33 and Arg556. The additional amine group showed interactions with Glu172 and Glu200. Based on transporter capacities and efficacies, it could be speculated that the functionalization of acetyl group at the C-17 position of the steroidal skeleton might be explored further to enable OAT1A2-mediated delivery of neurosteroids into the cells and also across the blood-brain barrier.
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spelling pubmed-84725972021-09-28 Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2 Adla, Santosh Kumar Tonduru, Arun Kumar Kronenberger, Thales Kudova, Eva Poso, Antti Huttunen, Kristiina M. Molecules Article In this study, we investigated the delivery of synthetic neurosteroids into MCF-7 human breast adenocarcinoma cells via Organic Anionic Transporting Polypeptides (OATPs) (pH 7.4 and 5.5) to identify the structural components required for OATP-mediated cellular uptake and to get insight into brain drug delivery. Then, we identified structure-uptake relationships using in-house developed OATP1A2 homology model to predict binding sites and modes for the ligands. These binding modes were studied by molecular dynamics simulations to rationalize the experimental results. Our results show that carboxylic acid needs to be at least at 3 carbon-carbon bonds distance from amide bond at the C-3 position of the androstane skeleton and have an amino group to avoid efflux transport. Replacement of hydroxyl group at C-3 with any of the 3, 4, and 5-carbon chained terminal carboxylic groups improved the affinity. We attribute this to polar interactions between carboxylic acid and side-chains of Lys33 and Arg556. The additional amine group showed interactions with Glu172 and Glu200. Based on transporter capacities and efficacies, it could be speculated that the functionalization of acetyl group at the C-17 position of the steroidal skeleton might be explored further to enable OAT1A2-mediated delivery of neurosteroids into the cells and also across the blood-brain barrier. MDPI 2021-09-17 /pmc/articles/PMC8472597/ /pubmed/34577133 http://dx.doi.org/10.3390/molecules26185662 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Adla, Santosh Kumar
Tonduru, Arun Kumar
Kronenberger, Thales
Kudova, Eva
Poso, Antti
Huttunen, Kristiina M.
Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
title Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
title_full Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
title_fullStr Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
title_full_unstemmed Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
title_short Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
title_sort neurosteroids: structure-uptake relationships and computational modeling of organic anion transporting polypeptides (oatp)1a2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472597/
https://www.ncbi.nlm.nih.gov/pubmed/34577133
http://dx.doi.org/10.3390/molecules26185662
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