New Computational Score Aims to Predict PROTAC Oral Absorption
- PROTACs (proteolysis-targeting chimeras) are large, polar, conformationally flexible molecules that fall outside classical Rule-of-5 space, making oral absorption difficult to predict from standard physicochemical filters alone.
- The paper introduces a fully computational scoring approach for oral absorption, intended to support rational, in silico PROTAC design earlier in the discovery process rather than relying mainly on measured properties.
- The score is built from computed molecular descriptors likely spanning size, polarity/lipophilicity balance, flexibility, and conformational behavior such as intramolecular folding — features previously linked to permeability in beyond-Rule-of-5 compounds.
- By combining these descriptors into a single predictive metric, the method aims to help chemists rank or triage PROTAC candidates for oral-absorption potential before synthesis.
- The authors position the score as a practical design-stage tool for guiding linker, warhead, and E3-ligand modifications toward improved oral bioavailability, complementing rather than replacing experimental permeability assays.
Any tool that lets me deprioritize a bad linker before I burn two weeks on synthesis and a Caco-2 run is welcome — PROTAC medchem cycles are brutal, and "just make it and test permeability" stops being an option once your library is 50+ analogs deep. That said, I've seen enough beyond-Ro5 permeability models oversell intramolecular H-bonding and chameleonic folding to stay skeptical until I see the validation set and how it handles my actual chemotypes — conformational behavior is exactly the thing computation still fakes worst. Where this actually helps is triage, not truth: rank candidates, flag the obvious dead-on-arrivals, then spend the wet-lab budget on the borderline cases. That's a real upgrade over eyeballing MW/PSA/cLogP cutoffs, which everyone in the PROTAC space already knows don't apply. If the descriptors genuinely capture folding propensity rather than just correlating with size, this could meaningfully shift where we spend linker SAR effort.