2026-10-14T07:47:20Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33916884 2026-09-18T00:07:48Z category_1 category_4 category_146 category_13 category_15 category_21 category_873 category_734 category_931 portal_63 item_type_3 month_year_09_2026

Toward Rational Design of Orally Bioavailable PROTACs: Development of a Fully Computational Oral Absorption Score Arman Fathizadeh (1668418) Erika M. V. Araujo (16033527) Nicholas T. Cockroft (6298784) Brett R. Beno (312375) Keith R. Hornberger (1982095) Biophysics Biochemistry Space Science Genetics Neuroscience Biotechnology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Information Systems not elsewhere classified similar literature methods remains challenging due rat data sets physicochemical property space lipophilicity terms consistent incorporating experimental information data sets studied may facilitate prioritization toward rational design early design stages extended molecular geometries orally bioavailable protacs orally absorbed protacs presynthetic prioritization molecular extension molecular dynamics targeting chimeras prior approaches potential framework potential benefit normalized radius introduce compass increased elongation improved absorption generalizable framework enhanced variant driven solely driven models conformational complexity based descriptors also developed across mouse 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. 2026-09-17T00:00:00Z Dataset Dataset 10.1021/acsmedchemlett.6c00305.s001 https://figshare.com/articles/dataset/Toward_Rational_Design_of_Orally_Bioavailable_PROTACs_Development_of_a_Fully_Computational_Oral_Absorption_Score/33916884 CC BY-NC 4.0