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Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients
BACKGROUND: Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a be...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412517/ https://www.ncbi.nlm.nih.gov/pubmed/37556043 http://dx.doi.org/10.1186/s43141-023-00538-1 |
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author | V., Janakiraman M., Sudhan Alsharif, Khalaf F. Halawani, Ibrahim F. Ahmed, Shiek S. S. J. Patil, Shankargouda |
author_facet | V., Janakiraman M., Sudhan Alsharif, Khalaf F. Halawani, Ibrahim F. Ahmed, Shiek S. S. J. Patil, Shankargouda |
author_sort | V., Janakiraman |
collection | PubMed |
description | BACKGROUND: Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a better affinity with NUDT15 protein and contributing stable conformation may benefit patients from leucopenia. Most frequent NUDT15 polymorphisms causing structure variability and their association with leukemia were screened. The selected protein variants and anti-cancer drug structures were collected. Further, molecular docking was performed between drugs and NUDT15 variants along with the wild-type. Finally, molecular dynamics were executed for 100 ns to understand the stability of the protein with the anti-cancer drug based on molecular trajectories. RESULTS: Three-dimensional structures of NUDT15 wild, the most frequent variants (Val18Ile, Arg139Cys, and Arg139), and the anti-cancer drugs (azathioprine, mercaptopurine, and thioguanine) were selected and retrieved from structure databases. On molecular docking the binding energies of anti-cancer drugs against NUDT15 structures ranged from − 5.0 to − 5.9 kcal/mol. Among them, azathioprine showed the highest affinities (− 7.3 kcal/mol) for the wild and variant structures. Additionally, the molecular dynamics suggest all analyzed NUDT15 were stable with azathioprine based on the dynamic trajectories. CONCLUSION: Our results suggest azathioprine could be the preferable anti-cancer drug for the population with NUDT15 variants that could effectively be hydrolyzed as evidenced by molecular docking and dynamic simulation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43141-023-00538-1. |
format | Online Article Text |
id | pubmed-10412517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-104125172023-08-11 Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients V., Janakiraman M., Sudhan Alsharif, Khalaf F. Halawani, Ibrahim F. Ahmed, Shiek S. S. J. Patil, Shankargouda J Genet Eng Biotechnol Research BACKGROUND: Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a better affinity with NUDT15 protein and contributing stable conformation may benefit patients from leucopenia. Most frequent NUDT15 polymorphisms causing structure variability and their association with leukemia were screened. The selected protein variants and anti-cancer drug structures were collected. Further, molecular docking was performed between drugs and NUDT15 variants along with the wild-type. Finally, molecular dynamics were executed for 100 ns to understand the stability of the protein with the anti-cancer drug based on molecular trajectories. RESULTS: Three-dimensional structures of NUDT15 wild, the most frequent variants (Val18Ile, Arg139Cys, and Arg139), and the anti-cancer drugs (azathioprine, mercaptopurine, and thioguanine) were selected and retrieved from structure databases. On molecular docking the binding energies of anti-cancer drugs against NUDT15 structures ranged from − 5.0 to − 5.9 kcal/mol. Among them, azathioprine showed the highest affinities (− 7.3 kcal/mol) for the wild and variant structures. Additionally, the molecular dynamics suggest all analyzed NUDT15 were stable with azathioprine based on the dynamic trajectories. CONCLUSION: Our results suggest azathioprine could be the preferable anti-cancer drug for the population with NUDT15 variants that could effectively be hydrolyzed as evidenced by molecular docking and dynamic simulation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43141-023-00538-1. Springer Berlin Heidelberg 2023-08-09 /pmc/articles/PMC10412517/ /pubmed/37556043 http://dx.doi.org/10.1186/s43141-023-00538-1 Text en © The Author(s) 2023 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 | Research V., Janakiraman M., Sudhan Alsharif, Khalaf F. Halawani, Ibrahim F. Ahmed, Shiek S. S. J. Patil, Shankargouda Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients |
title | Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients |
title_full | Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients |
title_fullStr | Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients |
title_full_unstemmed | Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients |
title_short | Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients |
title_sort | comparative assessment of anti-cancer drugs against nudt15 variants to prevent leucopenia side effect in leukemia patients |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412517/ https://www.ncbi.nlm.nih.gov/pubmed/37556043 http://dx.doi.org/10.1186/s43141-023-00538-1 |
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