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

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 bioavailability of VHL-based PROTACs with different linker methylation levels can be predicted throughout drug discovery. However, this requires specialized tools tailored to the challenges of PROTAC chemical space. Further work is needed to develop a robust, standardized, and automated predictive workflow.