ArticleACS medicinal chemistry letters2025
New Multiparameter Index Is a Strong Predictor of Oral Bioavailability for Heterobifunctional Degraders.
Article in ACS medicinal chemistry letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Development and application of a quantitative physicochemical model of P-gp substrate specificity.Journal of computer-aided molecular design · 2026Article
- Chemical Profile and Bioinsecticidal Nanoemulsion ofPlants (Basel, Switzerland) · 2026Article
- Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors.ACS medicinal chemistry letters · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- Unhooking the Hook: Optimization of the Aurora A Targeting PROTACJournal of medicinal chemistry · 2026Article
Corrections and comments
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Authors and funding
10 authors.
Funding
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Abstract
Ligand-directed degraders (LDDs) are heterobifunctional molecules that degrade proteins by engaging the ubiquitin-protein-ligase (E3) system. LDDs (also known as proteolysis-targeting chimeras) consist of a target-engaging moiety, an E3 ligase-binding moiety, and a bridging linker. Due to their size and physicochemical complexity, these molecules do not adhere to well-established rules of lead optimization. Achieving oral bioavailability remains a key challenge in the optimization of LDDs as therapeutic agents. In this study, we build on the previously established Balanced Permeability Index (BPI) (a metric that integrates size, polarity, and lipophilicity) by incorporating an additional descriptor to account for molecular shape. Our new combined metric, termed Bifunctional Bioavailability Index (BBI), can differentiate oral bioavailability of LDDs in our data set more effectively than polarity, lipophilicity, or size separately. Notably, BBI is also more effective than
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