The size matters? A computational tool to design bivalent ligands

Bioinformatics
Laura Pérez-BenitoLeonardo Pardo

Abstract

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. 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. Freely accessible from the Molecular Operating Environment svl exchange server (https://svl.chemcomp.com/). Supplementary data are available at Bioinformatics online.

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Citations

Aug 15, 2020·Chemistry : a European Journal·Paula MoralesNadine Jagerovic
Feb 18, 2021·Journal of Natural Products·Darius P ZlotosUlrike Holzgrabe
Apr 24, 2021·Journal of Medicinal Chemistry·Maria GalloDavid Andreu
Jun 10, 2021·Journal of Medicinal Chemistry·Troy A BemisMichael D Burkart
Aug 5, 2021·ACS Central Science·Frances P Rodriguez-Rivera, Samuel M Levi
Feb 5, 2019·Journal of Chemical Information and Modeling·Michael L Drummond, Christopher I Williams
Sep 25, 2020·Journal of Chemical Information and Modeling·Michael L DrummondChristopher I Williams
Sep 26, 2020·Journal of Chemical Information and Modeling·Daniel ZaidmanNir London
Jan 5, 2022·Journal of Medicinal Chemistry·Daniel PulidoMiriam Royo
Jan 11, 2022·Medicinal Research Reviews·Shipeng HeChunquan Sheng

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