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Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain
X-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3, -7 and -9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells’ death skipping. Inhibition of XIAP-B...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10343376/ https://www.ncbi.nlm.nih.gov/pubmed/37446817 http://dx.doi.org/10.3390/molecules28135155 |
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author | Farag, Marc Kieffer, Charline Guedeney, Nicolas Voisin-Chiret, Anne Sophie Sopkova-de Oliveira Santos, Jana |
author_facet | Farag, Marc Kieffer, Charline Guedeney, Nicolas Voisin-Chiret, Anne Sophie Sopkova-de Oliveira Santos, Jana |
author_sort | Farag, Marc |
collection | PubMed |
description | X-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3, -7 and -9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells’ death skipping. Inhibition of XIAP-BIR3 domain and caspase-9 interaction was raised as a promising strategy to restore apoptosis in malignancy treatment. However, XIAP-BIR3 antagonists also inhibit cIAP1-2 BIR3 domains, leading to serious side effects. In this study, we worked on a theoretical model that allowed us to design and optimize selective synthetic XIAP-BIR3 antagonists. Firstly, we assessed various MM-PBSA strategies to predict the XIAP-BIR3 binding affinities of synthetic ligands. Molecular dynamics simulations using hydrogen mass repartition as an additional parametrization with and without entropic term computed by the interaction entropy approach produced the best correlations. These simulations were then exploited to generate 3D pharmacophores. Following an optimization with a training dataset, five features were enough to model XIAP-BIR3 synthetic ligands binding to two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic groups. The correlation between pharmacophoric features and computed MM-PBSA free energy revealed nine residues as crucial for synthetic ligand binding: Thr308, Glu314, Trp323, Leu307, Asp309, Trp310, Gly306, Gln319 and Lys297. Ultimately, and three of them seemed interesting to use to improve XIAP-BR3 versus cIAP-BIR3 selectivity: Lys297, Thr308 and Asp309. |
format | Online Article Text |
id | pubmed-10343376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103433762023-07-14 Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain Farag, Marc Kieffer, Charline Guedeney, Nicolas Voisin-Chiret, Anne Sophie Sopkova-de Oliveira Santos, Jana Molecules Article X-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3, -7 and -9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells’ death skipping. Inhibition of XIAP-BIR3 domain and caspase-9 interaction was raised as a promising strategy to restore apoptosis in malignancy treatment. However, XIAP-BIR3 antagonists also inhibit cIAP1-2 BIR3 domains, leading to serious side effects. In this study, we worked on a theoretical model that allowed us to design and optimize selective synthetic XIAP-BIR3 antagonists. Firstly, we assessed various MM-PBSA strategies to predict the XIAP-BIR3 binding affinities of synthetic ligands. Molecular dynamics simulations using hydrogen mass repartition as an additional parametrization with and without entropic term computed by the interaction entropy approach produced the best correlations. These simulations were then exploited to generate 3D pharmacophores. Following an optimization with a training dataset, five features were enough to model XIAP-BIR3 synthetic ligands binding to two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic groups. The correlation between pharmacophoric features and computed MM-PBSA free energy revealed nine residues as crucial for synthetic ligand binding: Thr308, Glu314, Trp323, Leu307, Asp309, Trp310, Gly306, Gln319 and Lys297. Ultimately, and three of them seemed interesting to use to improve XIAP-BR3 versus cIAP-BIR3 selectivity: Lys297, Thr308 and Asp309. MDPI 2023-06-30 /pmc/articles/PMC10343376/ /pubmed/37446817 http://dx.doi.org/10.3390/molecules28135155 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Farag, Marc Kieffer, Charline Guedeney, Nicolas Voisin-Chiret, Anne Sophie Sopkova-de Oliveira Santos, Jana Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain |
title | Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain |
title_full | Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain |
title_fullStr | Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain |
title_full_unstemmed | Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain |
title_short | Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain |
title_sort | computational tool to design small synthetic inhibitors selective for xiap-bir3 domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10343376/ https://www.ncbi.nlm.nih.gov/pubmed/37446817 http://dx.doi.org/10.3390/molecules28135155 |
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