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In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization

The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozym...

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Autores principales: Ejaz, Syeda Abida, Saeed, Amna, Birmani, Pervez Rashid, Katubi, Khadijah Mohammedsalaeh, Elqahtani, Zainab Mufarreh, Al-Buriahi, M. S., Ujan, Rabail, Siddique, Farhan, Ahmed, Samia ben, Alrowaili, Z. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612481/
https://www.ncbi.nlm.nih.gov/pubmed/36301939
http://dx.doi.org/10.1371/journal.pone.0271602
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author Ejaz, Syeda Abida
Saeed, Amna
Birmani, Pervez Rashid
Katubi, Khadijah Mohammedsalaeh
Elqahtani, Zainab Mufarreh
Al-Buriahi, M. S.
Ujan, Rabail
Siddique, Farhan
Ahmed, Samia ben
Alrowaili, Z. A.
author_facet Ejaz, Syeda Abida
Saeed, Amna
Birmani, Pervez Rashid
Katubi, Khadijah Mohammedsalaeh
Elqahtani, Zainab Mufarreh
Al-Buriahi, M. S.
Ujan, Rabail
Siddique, Farhan
Ahmed, Samia ben
Alrowaili, Z. A.
author_sort Ejaz, Syeda Abida
collection PubMed
description The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozymes. Therefore, there is a need of selective inhibitors of both targets for the eradication of colon cancer. Currently, the study is focused on the exploration of two quinolone compounds i.e., (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinidine) and (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinine) as the potential inhibitors of AKR1B1 and AKR1B10 via detailed in-silico approach. The structural properties including vibrational frequencies, dipole moment, polarizability and the optimization energies were estimated using density functional theory (DFT) calculations; where both compounds were found chemically reactive. After that, the optimized structures were used for the molecular docking studies and here quinidine was found more selective towards AKR1B1 and quinine exhibited maximum inhibition of AKR1B10. The results of molecular docking studies were validated by molecular dynamics simulations which provided the deep insight of stability of protein ligand complex. At the end, the ADMET properties were determined to demonstrate the druglikeness properties of both selected compounds. These findings suggested further exploration of both compounds at molecular level using different in-vivo and in-vitro approaches that will lead to the designing of potential inhibitor of AKR1B1/AKR1B10 for curing colon cancer and related malignancies.
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spelling pubmed-96124812022-10-28 In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization Ejaz, Syeda Abida Saeed, Amna Birmani, Pervez Rashid Katubi, Khadijah Mohammedsalaeh Elqahtani, Zainab Mufarreh Al-Buriahi, M. S. Ujan, Rabail Siddique, Farhan Ahmed, Samia ben Alrowaili, Z. A. PLoS One Research Article The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozymes. Therefore, there is a need of selective inhibitors of both targets for the eradication of colon cancer. Currently, the study is focused on the exploration of two quinolone compounds i.e., (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinidine) and (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinine) as the potential inhibitors of AKR1B1 and AKR1B10 via detailed in-silico approach. The structural properties including vibrational frequencies, dipole moment, polarizability and the optimization energies were estimated using density functional theory (DFT) calculations; where both compounds were found chemically reactive. After that, the optimized structures were used for the molecular docking studies and here quinidine was found more selective towards AKR1B1 and quinine exhibited maximum inhibition of AKR1B10. The results of molecular docking studies were validated by molecular dynamics simulations which provided the deep insight of stability of protein ligand complex. At the end, the ADMET properties were determined to demonstrate the druglikeness properties of both selected compounds. These findings suggested further exploration of both compounds at molecular level using different in-vivo and in-vitro approaches that will lead to the designing of potential inhibitor of AKR1B1/AKR1B10 for curing colon cancer and related malignancies. Public Library of Science 2022-10-27 /pmc/articles/PMC9612481/ /pubmed/36301939 http://dx.doi.org/10.1371/journal.pone.0271602 Text en © 2022 Ejaz et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ejaz, Syeda Abida
Saeed, Amna
Birmani, Pervez Rashid
Katubi, Khadijah Mohammedsalaeh
Elqahtani, Zainab Mufarreh
Al-Buriahi, M. S.
Ujan, Rabail
Siddique, Farhan
Ahmed, Samia ben
Alrowaili, Z. A.
In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization
title In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization
title_full In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization
title_fullStr In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization
title_full_unstemmed In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization
title_short In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization
title_sort in-silico investigations of quinine and quinidine as potential inhibitors of akr1b1 and akr1b10: functional and structural characterization
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612481/
https://www.ncbi.nlm.nih.gov/pubmed/36301939
http://dx.doi.org/10.1371/journal.pone.0271602
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