Linker-Dependent Folding Rationalizes PROTAC Cell Permeability

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
molecular dynamics (MD) simulations independently to gain insights
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 a low solvent-accessible 3D polar surface
area in an apolar environment is correlated to high cell permeability.
The chemical nature and the flexibility of the linker were essential
for the PROTACs to populate folded conformations stabilized by intramolecular
hydrogen bonds, π–π interactions, 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.