Linker-dependent folding rationalizes PROTAC cell permeability

04 May 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Proteolysis targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, the outer limits of oral druggable space. We used NMR spectroscopy and MD simulations independently to gain insight into the origin of the differences in cell permeability displayed by three flexible cereblon PROTACs having closely related structures. Both methods revealed that the propensity of the PROTACs to adopt folded conformations with low solvent accessible 3D polar surface area in an apolar environment correlated to high cell permeability. The flexibility of the linker appeared essential for the PROTACs to populate folded conformations stabilized by intramolecular hydrogen bonds, pi-pi and van der Waals interactions. We conclude that MD simulations may be used for the prospective ranking of cell permeability in the design of cereblon PROTACs.


cell permeability
NMR spectroscopy
molecular dynamics simulations


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.