Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/204060
Title: | Lenalidomide Stabilizes Protein-Protein Complexes by Turning Labile Intermolecular H-Bonds into Robust Interactions |
Author: | Miñarro Lleonar, Marina Bertran-Mostazo, Andrea Duro Gómez, Jorge Barril Alonso, Xavier Juárez Jiménez, Jordi |
Keywords: | Dinàmica molecular Estabilitat dels medicaments Molecular dynamics Drug stability |
Issue Date: | 21-Apr-2023 |
Publisher: | American Chemical Society |
Abstract: | Targeted protein degradation is a promising therapeutic strategy, spearheaded by the anti-myeloma drugs lenalidomide and pomalidomide. These drugs stabilize very efficiently the complex between the E3 ligase Cereblon (CRBN) and several non-native client proteins (neosubstrates), including the transcription factors Ikaros and Aiolos and the enzyme Caseine Kinase 1 (CK1,), resulting in their degradation. Although the structures for these complexes have been determined, there are no evident interactions that can account for the high efficiency of formation of the ternary complex. We show that lenalidomide's stabilization of the CRBN-CK1 complex is largely due to hydrophobic shielding of intermolecular hydrogen bonds. We also find a quantitative relationship between hydrogen bond robustness and binding affinities of the ternary complexes. These results pave the way to further understand cooperativity effects in drug-induced protein-protein complexes and could help in the design of improved molecular glues and more efficient protein degraders. |
Note: | Reproducció del document publicat a: https://doi.org/10.1021/acs.jmedchem.2c01692 |
It is part of: | Journal of Medicinal Chemistry, 2023, vol. 66, num.9, p. 6037-6046 |
URI: | http://hdl.handle.net/2445/204060 |
Related resource: | https://doi.org/10.1021/acs.jmedchem.2c01692 |
ISSN: | 0022-2623 |
Appears in Collections: | Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica) |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
260545.pdf | 4.6 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License