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Solution Conformations Shed Light on PROTAC Cell Permeability.

ABSTRACT: 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, ?-? 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.

SUBMITTER: Atilaw Y

PROVIDER: S-EPMC7812666 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Solution Conformations Shed Light on PROTAC Cell Permeability.

Atilaw Yoseph Y Poongavanam Vasanthanathan V Svensson Nilsson Caroline C Nguyen Duy D Giese Anja A Meibom Daniel D Erdelyi Mate M Kihlberg Jan J

ACS medicinal chemistry letters 20201225 1

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 (<b>1</b>), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that <b>1</b> populates elon ...[more]

PMID: 33488971

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Dataset Information

Solution Conformations Shed Light on PROTAC Cell Permeability.

Publications

Solution Conformations Shed Light on PROTAC Cell Permeability.

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