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Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors
The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199216/ https://www.ncbi.nlm.nih.gov/pubmed/34072837 http://dx.doi.org/10.3390/ijms22115910 |
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author | Luise, Chiara Robaa, Dina Regenass, Pierre Maurer, David Ostrovskyi, Dmytro Seifert, Ludwig Bacher, Johannes Burgahn, Teresa Wagner, Tobias Seitz, Johannes Greschik, Holger Park, Kwang-Su Xiong, Yan Jin, Jian Schüle, Roland Breit, Bernhard Jung, Manfred Sippl, Wolfgang |
author_facet | Luise, Chiara Robaa, Dina Regenass, Pierre Maurer, David Ostrovskyi, Dmytro Seifert, Ludwig Bacher, Johannes Burgahn, Teresa Wagner, Tobias Seitz, Johannes Greschik, Holger Park, Kwang-Su Xiong, Yan Jin, Jian Schüle, Roland Breit, Bernhard Jung, Manfred Sippl, Wolfgang |
author_sort | Luise, Chiara |
collection | PubMed |
description | The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings. |
format | Online Article Text |
id | pubmed-8199216 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81992162021-06-14 Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors Luise, Chiara Robaa, Dina Regenass, Pierre Maurer, David Ostrovskyi, Dmytro Seifert, Ludwig Bacher, Johannes Burgahn, Teresa Wagner, Tobias Seitz, Johannes Greschik, Holger Park, Kwang-Su Xiong, Yan Jin, Jian Schüle, Roland Breit, Bernhard Jung, Manfred Sippl, Wolfgang Int J Mol Sci Article The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings. MDPI 2021-05-31 /pmc/articles/PMC8199216/ /pubmed/34072837 http://dx.doi.org/10.3390/ijms22115910 Text en © 2021 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 Luise, Chiara Robaa, Dina Regenass, Pierre Maurer, David Ostrovskyi, Dmytro Seifert, Ludwig Bacher, Johannes Burgahn, Teresa Wagner, Tobias Seitz, Johannes Greschik, Holger Park, Kwang-Su Xiong, Yan Jin, Jian Schüle, Roland Breit, Bernhard Jung, Manfred Sippl, Wolfgang Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors |
title | Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors |
title_full | Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors |
title_fullStr | Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors |
title_full_unstemmed | Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors |
title_short | Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors |
title_sort | structure-based design, docking and binding free energy calculations of a366 derivatives as spindlin1 inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199216/ https://www.ncbi.nlm.nih.gov/pubmed/34072837 http://dx.doi.org/10.3390/ijms22115910 |
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