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In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded by CSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587039/ https://www.ncbi.nlm.nih.gov/pubmed/36271116 http://dx.doi.org/10.1038/s41598-022-21546-0 |
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author | Alsagaby, Suliman A. Iqbal, Danish Ahmad, Iqrar Patel, Harun Mir, Shabir Ahmad Madkhali, Yahya Awaji Oyouni, Atif Abdulwahab A. Hawsawi, Yousef M. Alhumaydhi, Fahad A. Alshehri, Bader Alturaiki, Wael Alanazi, Bader Mir, Manzoor Ahmad Al Abdulmonem, Waleed |
author_facet | Alsagaby, Suliman A. Iqbal, Danish Ahmad, Iqrar Patel, Harun Mir, Shabir Ahmad Madkhali, Yahya Awaji Oyouni, Atif Abdulwahab A. Hawsawi, Yousef M. Alhumaydhi, Fahad A. Alshehri, Bader Alturaiki, Wael Alanazi, Bader Mir, Manzoor Ahmad Al Abdulmonem, Waleed |
author_sort | Alsagaby, Suliman A. |
collection | PubMed |
description | Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded by CSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools were used to search for a competent inhibitor of CK2α from fungal metabolites that could be proposed for CLL therapy. In CLL patients, high-expression of CSNK2A1 was associated with early need for therapy (n = 130, p < 0.0001) and short overall survival (OS; n = 107, p = 0.005). Consistently, bioinformatics analyses showed CSNK2A1 to associate with/play roles in CLL proliferation and survival-dependent pathways. Furthermore, PPI network analysis identified interaction partners of CK2α (PPI enrichment p value = 1 × 10(–16)) that associated with early need for therapy (n = 130, p < 0.003) and have been known to heavily impact on the progression of CLL. These findings constructed a rational for targeting CK2α for CLL therapy. Consequently, computational analyses reported 35 fungal metabolites out of 5820 (filtered from 19,967 metabolites) to have lower binding energy (ΔG: − 10.9 to − 11.7 kcal/mol) and better binding affinity (Kd: 9.77 × 10(7) M(−1) to 3.77 × 10(8) M(−1)) compared with the native ligand (ΔG: − 10.8, Kd: 8.3 × 10(7) M−(−1)). Furthermore, molecular dynamics simulation study established that Butyl Xanalterate-CK2α complex continuously remained stable throughout the simulation time (100 ns). Moreover, Butyl Xanalterate interacted with most of the catalytic residues, where complex was stabilized by more than 65% hydrogen bond interactions, and a significant hydrophobic interaction with residue Phe113. Here, high-expression of CSNK2A1 was implicated in the progression and poor prognosis of CLL, making it a potential therapeutic target in the disease. Butyl Xanalterate showed stable and strong interactions with CK2α, thus we propose it as a competitive inhibitor of CK2α for CLL therapy. |
format | Online Article Text |
id | pubmed-9587039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-95870392022-10-23 In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia Alsagaby, Suliman A. Iqbal, Danish Ahmad, Iqrar Patel, Harun Mir, Shabir Ahmad Madkhali, Yahya Awaji Oyouni, Atif Abdulwahab A. Hawsawi, Yousef M. Alhumaydhi, Fahad A. Alshehri, Bader Alturaiki, Wael Alanazi, Bader Mir, Manzoor Ahmad Al Abdulmonem, Waleed Sci Rep Article Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded by CSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools were used to search for a competent inhibitor of CK2α from fungal metabolites that could be proposed for CLL therapy. In CLL patients, high-expression of CSNK2A1 was associated with early need for therapy (n = 130, p < 0.0001) and short overall survival (OS; n = 107, p = 0.005). Consistently, bioinformatics analyses showed CSNK2A1 to associate with/play roles in CLL proliferation and survival-dependent pathways. Furthermore, PPI network analysis identified interaction partners of CK2α (PPI enrichment p value = 1 × 10(–16)) that associated with early need for therapy (n = 130, p < 0.003) and have been known to heavily impact on the progression of CLL. These findings constructed a rational for targeting CK2α for CLL therapy. Consequently, computational analyses reported 35 fungal metabolites out of 5820 (filtered from 19,967 metabolites) to have lower binding energy (ΔG: − 10.9 to − 11.7 kcal/mol) and better binding affinity (Kd: 9.77 × 10(7) M(−1) to 3.77 × 10(8) M(−1)) compared with the native ligand (ΔG: − 10.8, Kd: 8.3 × 10(7) M−(−1)). Furthermore, molecular dynamics simulation study established that Butyl Xanalterate-CK2α complex continuously remained stable throughout the simulation time (100 ns). Moreover, Butyl Xanalterate interacted with most of the catalytic residues, where complex was stabilized by more than 65% hydrogen bond interactions, and a significant hydrophobic interaction with residue Phe113. Here, high-expression of CSNK2A1 was implicated in the progression and poor prognosis of CLL, making it a potential therapeutic target in the disease. Butyl Xanalterate showed stable and strong interactions with CK2α, thus we propose it as a competitive inhibitor of CK2α for CLL therapy. Nature Publishing Group UK 2022-10-21 /pmc/articles/PMC9587039/ /pubmed/36271116 http://dx.doi.org/10.1038/s41598-022-21546-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Alsagaby, Suliman A. Iqbal, Danish Ahmad, Iqrar Patel, Harun Mir, Shabir Ahmad Madkhali, Yahya Awaji Oyouni, Atif Abdulwahab A. Hawsawi, Yousef M. Alhumaydhi, Fahad A. Alshehri, Bader Alturaiki, Wael Alanazi, Bader Mir, Manzoor Ahmad Al Abdulmonem, Waleed In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia |
title | In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia |
title_full | In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia |
title_fullStr | In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia |
title_full_unstemmed | In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia |
title_short | In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia |
title_sort | in silico investigations identified butyl xanalterate to competently target ck2α (csnk2a1) for therapy of chronic lymphocytic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587039/ https://www.ncbi.nlm.nih.gov/pubmed/36271116 http://dx.doi.org/10.1038/s41598-022-21546-0 |
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