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

2025/07/31 by Diego Garcia Jimenez, Diego García Jiménez, Giuseppe Ermondi +5 · 1 voice · 4 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Histone Deacetylase Inhibitors Research #Peptidase Inhibition and Analysis #Protein Degradation and Inhibitors

paper · pdf · doi:10.1021/acs.jmedchem.5c01497

openalex publication_date 2025/08/01 · openalex created_date 2025/08/02 · openalex updated_date 2026/07/28

Abstract

High Resolution Image Download MS PowerPoint Slide 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 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.

Cited by

• Smart Integration of Structural Biology and Medicinal Chemistry to Unlock Target‐Driven Drug Discovery
• Advances in computational methods for PROTAC drug discovery
• Diastereomeric Branched-Ester dBET1 Analogs Exhibit Conformation-Dependent Differences in Passive Membrane Permeability. [europepmc]
• Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors. [europepmc]

Discussions

• 🚀 New J. Med. Chem. study: Linker methylation boosts oral bioavailability of VHL-PROTACs. 📊 #alvaDesc linked chemical space to PK for smarter design in #bRo5. 📄 Read the paper: doi.org/10.1021/acs [bsky, 1 points, 0 comments]

Related

• Predicting PROTAC Oral Bioavailability with Physics-Based Foundation Model Finetuning
• Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer
• Advances in computational methods for PROTAC drug discovery
• A Comprehensive Review of Emerging Approaches in Machine Learning for De Novo PROTAC Design
• PROTAC-Splitter: A Machine Learning Framework for Automated Identification of PROTAC Substructures