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Solution Conformations Shed Light on PROTAC Cell Permeability
[Image: see text] Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell perme...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812666/ https://www.ncbi.nlm.nih.gov/pubmed/33488971 http://dx.doi.org/10.1021/acsmedchemlett.0c00556 |
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author | Atilaw, Yoseph Poongavanam, Vasanthanathan Svensson Nilsson, Caroline Nguyen, Duy Giese, Anja Meibom, Daniel Erdelyi, Mate Kihlberg, Jan |
author_facet | Atilaw, Yoseph Poongavanam, Vasanthanathan Svensson Nilsson, Caroline Nguyen, Duy Giese, Anja Meibom, Daniel Erdelyi, Mate Kihlberg, Jan |
author_sort | Atilaw, Yoseph |
collection | PubMed |
description | [Image: see text] Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells. |
format | Online Article Text |
id | pubmed-7812666 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-78126662021-01-21 Solution Conformations Shed Light on PROTAC Cell Permeability Atilaw, Yoseph Poongavanam, Vasanthanathan Svensson Nilsson, Caroline Nguyen, Duy Giese, Anja Meibom, Daniel Erdelyi, Mate Kihlberg, Jan ACS Med Chem Lett [Image: see text] Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells. American Chemical Society 2020-12-25 /pmc/articles/PMC7812666/ /pubmed/33488971 http://dx.doi.org/10.1021/acsmedchemlett.0c00556 Text en © 2020 The Authors. Published by American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Atilaw, Yoseph Poongavanam, Vasanthanathan Svensson Nilsson, Caroline Nguyen, Duy Giese, Anja Meibom, Daniel Erdelyi, Mate Kihlberg, Jan Solution Conformations Shed Light on PROTAC Cell Permeability |
title | Solution Conformations Shed Light on PROTAC Cell Permeability |
title_full | Solution Conformations Shed Light on PROTAC Cell Permeability |
title_fullStr | Solution Conformations Shed Light on PROTAC Cell Permeability |
title_full_unstemmed | Solution Conformations Shed Light on PROTAC Cell Permeability |
title_short | Solution Conformations Shed Light on PROTAC Cell Permeability |
title_sort | solution conformations shed light on protac cell permeability |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812666/ https://www.ncbi.nlm.nih.gov/pubmed/33488971 http://dx.doi.org/10.1021/acsmedchemlett.0c00556 |
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