In This Issue, Volume 16, Issue 4

Le résumé fourni par la source

Proteolysis-targeting chimeras (PROTACs) are becoming increasingly popular modalities in drug discovery.However, because of their chimeric nature, PROTACs typically fall in Beyond Rule of Five chemical space, which can limit the permeability and bioavailability.Moreover, due in part to their size, highly structurally related PROTACs can have vastly different drug properties.In this Issue, Poongavanam et al. (DOI: 10.1021/acsmedchemlett.5c00068) analyze one such case of two PROTACs that differ by only two heavy atoms in the linker region.Despite their structural similarity, the PROTAC bearing a PEG linker is drastically more permeable than the all-carbon variant in PAMPA and cell-based assays.Using molecular dynamic (MD) simulations in explicit water and chloroform, the conformational landscape of each PROTAC was modeled and later experimentally confirmed via NMR.While the more permeable alkyl linker PROTAC adopts similar, folded conformations in both polar and nonpolar environments, the less permeable PEG linker PROTAC undergoes a conformational change to an extended conformation in nonpolar environments.Somewhat paradoxically, this extended conformation in the nonpolar environment increases the surface-accessible 3D polar surface area, which likely accounts for PROTAC's reduced permeability across lipid membranes.This investigation provides further proof that studying the conformational ensembles of highly flexible molecules like PROTACs is important for understanding their properties, which in turn can facilitate their optimization.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.