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Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction
MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent a...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351717/ https://www.ncbi.nlm.nih.gov/pubmed/32651397 http://dx.doi.org/10.1038/s41598-020-67510-8 |
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author | Rasafar, Nasim Barzegar, Abolfazl Mehdizadeh Aghdam, Elnaz |
author_facet | Rasafar, Nasim Barzegar, Abolfazl Mehdizadeh Aghdam, Elnaz |
author_sort | Rasafar, Nasim |
collection | PubMed |
description | MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent and dual inhibitors of MDM2/X. Correspondingly, MD simulation was performed on the experimentally confirmed peptides, comprising p53, pDI, pDIQ, PMI, and computationally screened mutant pDI and pDIQ. A follow-up secondary structure analysis showed the last three C-terminal residues provide the helicity reservation of peptides bound to MDM2/X. Furthermore, a delicate residue-residue examination displayed Met 11 and Ser12 in the modified peptides contribute significantly to dual inhibition of MDM2/X. Additionally, the peptides_MDM2/X complexes’ ΔG(binding) extracted by the umbrella sampling method were in agreement with the pattern of their experimental affinity values. It was concluded the screened pDI mutants were considered as suitable anti-MDM2/X peptides, and the data obtained could be exploited as the theoretical structure-based guide for rational peptide design. Taking account of results, the suitable C-terminal residues of p53-based peptides especially Met11, and Ser12, as well as higher umbrella sampling, generated ΔG(binding) to MDM2/X would be considered as the positive structural markers of a promising anti-cancer agent. |
format | Online Article Text |
id | pubmed-7351717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73517172020-07-14 Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction Rasafar, Nasim Barzegar, Abolfazl Mehdizadeh Aghdam, Elnaz Sci Rep Original Research MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent and dual inhibitors of MDM2/X. Correspondingly, MD simulation was performed on the experimentally confirmed peptides, comprising p53, pDI, pDIQ, PMI, and computationally screened mutant pDI and pDIQ. A follow-up secondary structure analysis showed the last three C-terminal residues provide the helicity reservation of peptides bound to MDM2/X. Furthermore, a delicate residue-residue examination displayed Met 11 and Ser12 in the modified peptides contribute significantly to dual inhibition of MDM2/X. Additionally, the peptides_MDM2/X complexes’ ΔG(binding) extracted by the umbrella sampling method were in agreement with the pattern of their experimental affinity values. It was concluded the screened pDI mutants were considered as suitable anti-MDM2/X peptides, and the data obtained could be exploited as the theoretical structure-based guide for rational peptide design. Taking account of results, the suitable C-terminal residues of p53-based peptides especially Met11, and Ser12, as well as higher umbrella sampling, generated ΔG(binding) to MDM2/X would be considered as the positive structural markers of a promising anti-cancer agent. Nature Publishing Group UK 2020-07-10 /pmc/articles/PMC7351717/ /pubmed/32651397 http://dx.doi.org/10.1038/s41598-020-67510-8 Text en © The Author(s) 2020 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 | Original Research Rasafar, Nasim Barzegar, Abolfazl Mehdizadeh Aghdam, Elnaz Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction |
title | Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction |
title_full | Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction |
title_fullStr | Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction |
title_full_unstemmed | Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction |
title_short | Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction |
title_sort | structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-mdm2/x interaction |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351717/ https://www.ncbi.nlm.nih.gov/pubmed/32651397 http://dx.doi.org/10.1038/s41598-020-67510-8 |
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