Abstract
The ability to adopt folded conformations that have a low solvent-accessible 3D polar surface area has been found to be important for PROTACs to display a high passive cell permeability. We have studied two VHL PROTACs that differ only by the replacement of two methylene groups in the linker by oxygen atoms but that displayed vast differences in their cell permeability. MD simulations and NMR spectroscopy revealed an unexpected, environment-dependent conformational behavior for the low-permeability PROTAC that has an alkyl linker. Hydrophobic interactions enforced extended and polar conformations for this PROTAC in nonpolar media, explaining its low cell permeability. In water, hydrophobic collapse around the linker led to folded and less polar conformations. In contrast, the highly permeable PROTAC having a PEG linker adopted conformations of similar shapes and polarities in polar and nonpolar environments.