Linker Methylation as a Strategy to Enhance PROTAC Oral Bioavailability: Insights from Molecular Properties and Conformational Analysis.

ABSTRACT: In this study, we profiled 11 structurally related von Hippel-Lindau (VHL)-based proteolysis-targeting chimeras (PROTACs), evaluating in vivo pharmacokinetics in mice (oral bioavailability and clearance), in vitro ADME properties (solubility, permeability, and efflux ratio), and key physicochemical traits (polarity, lipophilicity, and chameleonicity). While Caco-2 permeability did not correlate with oral bioavailability (F%), the efflux ratio (ER) proved a strong predictor. The ER could also be estimated using the chromatographic descriptor log k'80 PLRP-S. Conformational sampling and molecular dynamics in polar and nonpolar environments showed that linker methylation drives chameleonic folding, influencing ER and, in turn, F%. Overall, our results show that the oral bioavail

SUBMITTER: Garcia Jimenez D 

PROVIDER: S-EPMC12362582 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature