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The size matters? A computational tool to design bivalent ligands

MOTIVATION: Bivalent ligands are increasingly important such as for targeting G protein-coupled receptor (GPCR) dimers or proteolysis targeting chimeras (PROTACs). They contain two pharmacophoric units that simultaneously bind in their corresponding binding sites, connected with a spacer chain. Here...

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Autores principales: Pérez-Benito, Laura, Henry, Andrew, Matsoukas, Minos-Timotheos, Lopez, Laura, Pulido, Daniel, Royo, Miriam, Cordomí, Arnau, Tresadern, Gary, Pardo, Leonardo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223368/
https://www.ncbi.nlm.nih.gov/pubmed/29850769
http://dx.doi.org/10.1093/bioinformatics/bty422
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author Pérez-Benito, Laura
Henry, Andrew
Matsoukas, Minos-Timotheos
Lopez, Laura
Pulido, Daniel
Royo, Miriam
Cordomí, Arnau
Tresadern, Gary
Pardo, Leonardo
author_facet Pérez-Benito, Laura
Henry, Andrew
Matsoukas, Minos-Timotheos
Lopez, Laura
Pulido, Daniel
Royo, Miriam
Cordomí, Arnau
Tresadern, Gary
Pardo, Leonardo
author_sort Pérez-Benito, Laura
collection PubMed
description MOTIVATION: Bivalent ligands are increasingly important such as for targeting G protein-coupled receptor (GPCR) dimers or proteolysis targeting chimeras (PROTACs). They contain two pharmacophoric units that simultaneously bind in their corresponding binding sites, connected with a spacer chain. Here, we report a molecular modelling tool that links the pharmacophore units via the shortest pathway along the receptors van der Waals surface and then scores the solutions providing prioritization for the design of new bivalent ligands. RESULTS: Bivalent ligands of known dimers of GPCRs, PROTACs and a model bivalent antibody/antigen system were analysed. The tool could rapidly assess the preferred linker length for the different systems and recapitulated the best reported results. In the case of GPCR dimers the results suggest that in some cases these ligands might bind to a secondary binding site at the extracellular entrance (vestibule or allosteric site) instead of the orthosteric binding site. AVAILABILITY AND IMPLEMENTATION: Freely accessible from the Molecular Operating Environment svl exchange server (https://svl.chemcomp.com/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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spelling pubmed-62233682018-11-14 The size matters? A computational tool to design bivalent ligands Pérez-Benito, Laura Henry, Andrew Matsoukas, Minos-Timotheos Lopez, Laura Pulido, Daniel Royo, Miriam Cordomí, Arnau Tresadern, Gary Pardo, Leonardo Bioinformatics Original Papers MOTIVATION: Bivalent ligands are increasingly important such as for targeting G protein-coupled receptor (GPCR) dimers or proteolysis targeting chimeras (PROTACs). They contain two pharmacophoric units that simultaneously bind in their corresponding binding sites, connected with a spacer chain. Here, we report a molecular modelling tool that links the pharmacophore units via the shortest pathway along the receptors van der Waals surface and then scores the solutions providing prioritization for the design of new bivalent ligands. RESULTS: Bivalent ligands of known dimers of GPCRs, PROTACs and a model bivalent antibody/antigen system were analysed. The tool could rapidly assess the preferred linker length for the different systems and recapitulated the best reported results. In the case of GPCR dimers the results suggest that in some cases these ligands might bind to a secondary binding site at the extracellular entrance (vestibule or allosteric site) instead of the orthosteric binding site. AVAILABILITY AND IMPLEMENTATION: Freely accessible from the Molecular Operating Environment svl exchange server (https://svl.chemcomp.com/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. Oxford University Press 2018-11-15 2018-05-29 /pmc/articles/PMC6223368/ /pubmed/29850769 http://dx.doi.org/10.1093/bioinformatics/bty422 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Papers
Pérez-Benito, Laura
Henry, Andrew
Matsoukas, Minos-Timotheos
Lopez, Laura
Pulido, Daniel
Royo, Miriam
Cordomí, Arnau
Tresadern, Gary
Pardo, Leonardo
The size matters? A computational tool to design bivalent ligands
title The size matters? A computational tool to design bivalent ligands
title_full The size matters? A computational tool to design bivalent ligands
title_fullStr The size matters? A computational tool to design bivalent ligands
title_full_unstemmed The size matters? A computational tool to design bivalent ligands
title_short The size matters? A computational tool to design bivalent ligands
title_sort size matters? a computational tool to design bivalent ligands
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223368/
https://www.ncbi.nlm.nih.gov/pubmed/29850769
http://dx.doi.org/10.1093/bioinformatics/bty422
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