Toward Rational Design of Orally Bioavailable PROTACs: Development of a Fully Computational Oral Absorption Score.

Achieving adequate oral absorption for proteolysis-targeting chimeras (PROTACs) remains challenging due to their size, polarity, and conformational complexity. While existing approaches often rely on physicochemical property space or chameleonicity-driven models, a generalizable framework for guiding compound design prior to synthesis is lacking. Here, we introduce comPASS, a fully computational scoring function derived from molecular dynamics-based descriptors that is designed to capture the balance between molecular extension and exposed polarity through normalized radius of gyration and three-dimensional polar surface area of PROTACs. Across mouse and rat data sets, comPASS shows consistent predictive performance and may facilitate prioritization of compounds at early design stages. We further show that within the data sets studied, extended molecular geometries are associated with improved absorption, when increased elongation is not driven solely by increases in molecular size. To assess the potential benefit of incorporating experimental information, we also developed an enhanced variant, ePASS, which incorporates experimental polar surface area (EPSA) and lipophilicity terms consistent with prior approaches and shows promising predictive performance relative to similar literature methods. Together, these results establish practical guidance for presynthetic prioritization of PROTACs and provide a potential framework for guiding the design of orally absorbed PROTACs.