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...
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MDPI AG
2023-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/13/5155 |
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| author | Marc Farag Charline Kieffer Nicolas Guedeney Anne Sophie Voisin-Chiret Jana Sopkova-de Oliveira Santos |
| author_facet | Marc Farag Charline Kieffer Nicolas Guedeney Anne Sophie Voisin-Chiret Jana Sopkova-de Oliveira Santos |
| author_sort | Marc Farag |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T01:33:44Z |
| format | Article |
| id | doaj.art-e94df2824aed43ca9b7361ce247907c4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T01:33:44Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e94df2824aed43ca9b7361ce247907c42023-11-18T17:09:00ZengMDPI AGMolecules1420-30492023-06-012813515510.3390/molecules28135155Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 DomainMarc Farag0Charline Kieffer1Nicolas Guedeney2Anne Sophie Voisin-Chiret3Jana Sopkova-de Oliveira Santos4Normandie Univ., UNICAEN, CERMN, 14000 Caen, FranceNormandie Univ., UNICAEN, CERMN, 14000 Caen, FranceNormandie Univ., UNICAEN, CERMN, 14000 Caen, FranceNormandie Univ., UNICAEN, CERMN, 14000 Caen, FranceNormandie Univ., UNICAEN, CERMN, 14000 Caen, FranceX-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.https://www.mdpi.com/1420-3049/28/13/5155XIAP-BIR3synthetic inhibitormolecular dynamicsMM-PBSA free energy prediction3D Pharmacophore |
| spellingShingle | Marc Farag Charline Kieffer Nicolas Guedeney Anne Sophie Voisin-Chiret Jana Sopkova-de Oliveira Santos Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain Molecules XIAP-BIR3 synthetic inhibitor molecular dynamics MM-PBSA free energy prediction 3D Pharmacophore |
| 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 | XIAP-BIR3 synthetic inhibitor molecular dynamics MM-PBSA free energy prediction 3D Pharmacophore |
| url | https://www.mdpi.com/1420-3049/28/13/5155 |
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