The size matters? A computational tool to design bivalent ligands

Laura Pérez-Benito, Andrew Henry, Minos Timotheos Matsoukas, Laura Lopez, Daniel Pulido, Miriam Royo, Arnau Cordomí, Gary Tresadern, Leonardo Pardo

Research output: Contribution to journalArticleResearch

4 Citations (Scopus)

Abstract

© The Author(s) 2018. Published by Oxford University Press. 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 informationSupplementary dataare available at Bioinformatics online.
Original languageEnglish
Pages (from-to)3857-3863
JournalBioinformatics
Volume34
DOIs
Publication statusPublished - 15 Nov 2018

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    Pérez-Benito, L., Henry, A., Matsoukas, M. T., Lopez, L., Pulido, D., Royo, M., Cordomí, A., Tresadern, G., & Pardo, L. (2018). The size matters? A computational tool to design bivalent ligands. Bioinformatics, 34, 3857-3863. https://doi.org/10.1093/bioinformatics/bty422