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Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer
Multidrug resistance (MDR) is the major cause, by which cancer cells expel the drugs out, developing a challenge against the current chemotherapeutic drugs regime. This mechanism is attributed to the over expression of ABC transporters like MRP1 on the surface of cells. Since nucleotide binding doma...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086895/ https://www.ncbi.nlm.nih.gov/pubmed/30097643 http://dx.doi.org/10.1038/s41598-018-30420-x |
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author | Dhasmana, Divya Singh, Ashutosh Shukla, Rohit Tripathi, Timir Garg, Neha |
author_facet | Dhasmana, Divya Singh, Ashutosh Shukla, Rohit Tripathi, Timir Garg, Neha |
author_sort | Dhasmana, Divya |
collection | PubMed |
description | Multidrug resistance (MDR) is the major cause, by which cancer cells expel the drugs out, developing a challenge against the current chemotherapeutic drugs regime. This mechanism is attributed to the over expression of ABC transporters like MRP1 on the surface of cells. Since nucleotide binding domains (NBD) of ABC transporters are the site of ATP binding and hydrolysis, thereby in this study we have targeted NBD1 of MRP1using molecular docking and molecular dynamic simulations (MDS). The compounds present in the FDA approved library were docked against NBD1 of the human multidrug resistance associated protein 1 (PDB ID: 2CBZ). For the docking studies, Standard Precision and Extra Precision methods were employed. After the EP docking studies, ligands showed an extremely low docking score that was indicative of very high binding affinity of the ligands to the NBD. Apart from the low docking score, another short listing criterion in simulation studies was the interaction of incoming ligand with the desired conserved residues of NDB involved in ATP binding and hydrolysis. Based on these measures, potassium citrate (DB09125) and technetium Tc-99m medronate (DB09138) were chosen and subjected to 100 ns simulation studies. From the MDS study we concluded that between these two compounds, potassium citrate is a better candidate for targeting MRP1. |
format | Online Article Text |
id | pubmed-6086895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60868952018-08-16 Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer Dhasmana, Divya Singh, Ashutosh Shukla, Rohit Tripathi, Timir Garg, Neha Sci Rep Article Multidrug resistance (MDR) is the major cause, by which cancer cells expel the drugs out, developing a challenge against the current chemotherapeutic drugs regime. This mechanism is attributed to the over expression of ABC transporters like MRP1 on the surface of cells. Since nucleotide binding domains (NBD) of ABC transporters are the site of ATP binding and hydrolysis, thereby in this study we have targeted NBD1 of MRP1using molecular docking and molecular dynamic simulations (MDS). The compounds present in the FDA approved library were docked against NBD1 of the human multidrug resistance associated protein 1 (PDB ID: 2CBZ). For the docking studies, Standard Precision and Extra Precision methods were employed. After the EP docking studies, ligands showed an extremely low docking score that was indicative of very high binding affinity of the ligands to the NBD. Apart from the low docking score, another short listing criterion in simulation studies was the interaction of incoming ligand with the desired conserved residues of NDB involved in ATP binding and hydrolysis. Based on these measures, potassium citrate (DB09125) and technetium Tc-99m medronate (DB09138) were chosen and subjected to 100 ns simulation studies. From the MDS study we concluded that between these two compounds, potassium citrate is a better candidate for targeting MRP1. Nature Publishing Group UK 2018-08-10 /pmc/articles/PMC6086895/ /pubmed/30097643 http://dx.doi.org/10.1038/s41598-018-30420-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dhasmana, Divya Singh, Ashutosh Shukla, Rohit Tripathi, Timir Garg, Neha Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer |
title | Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer |
title_full | Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer |
title_fullStr | Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer |
title_full_unstemmed | Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer |
title_short | Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer |
title_sort | targeting nucleotide binding domain of multidrug resistance-associated protein-1 (mrp1) for the reversal of multi drug resistance in cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086895/ https://www.ncbi.nlm.nih.gov/pubmed/30097643 http://dx.doi.org/10.1038/s41598-018-30420-x |
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