Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783369389557415936 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6223368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT perezbenitolaura thesizemattersacomputationaltooltodesignbivalentligands AT henryandrew thesizemattersacomputationaltooltodesignbivalentligands AT matsoukasminostimotheos thesizemattersacomputationaltooltodesignbivalentligands AT lopezlaura thesizemattersacomputationaltooltodesignbivalentligands AT pulidodaniel thesizemattersacomputationaltooltodesignbivalentligands AT royomiriam thesizemattersacomputationaltooltodesignbivalentligands AT cordomiarnau thesizemattersacomputationaltooltodesignbivalentligands AT tresaderngary thesizemattersacomputationaltooltodesignbivalentligands AT pardoleonardo thesizemattersacomputationaltooltodesignbivalentligands AT perezbenitolaura sizemattersacomputationaltooltodesignbivalentligands AT henryandrew sizemattersacomputationaltooltodesignbivalentligands AT matsoukasminostimotheos sizemattersacomputationaltooltodesignbivalentligands AT lopezlaura sizemattersacomputationaltooltodesignbivalentligands AT pulidodaniel sizemattersacomputationaltooltodesignbivalentligands AT royomiriam sizemattersacomputationaltooltodesignbivalentligands AT cordomiarnau sizemattersacomputationaltooltodesignbivalentligands AT tresaderngary sizemattersacomputationaltooltodesignbivalentligands AT pardoleonardo sizemattersacomputationaltooltodesignbivalentligands |