New Multiparameter Index Is a Strong Predictor of Oral Bioavailability for Heterobifunctional Degraders

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Ligand-directed degraders (LDDs), or proteolysis-targeting chimeras, are heterobifunctional molecules designed to degrade target proteins via the ubiquitin-protein-ligase (E3) system.
• LDDs comprise a target-binding moiety, an E3 ligase-binding moiety, and a linker, presenting significant challenges in lead optimization due to their size and physicochemical complexity.
• Achieving oral bioavailability is a critical hurdle in developing LDDs as therapeutic agents.

Purpose of the Study:

• To develop a novel computational metric for predicting the oral bioavailability of LDDs.
• To enhance existing predictive models by incorporating molecular shape alongside size, polarity, and lipophilicity.

Main Methods:

• The study builds upon the Balanced Permeability Index (BPI) by introducing a new descriptor for molecular shape.
• A combined metric, the Bifunctional Bioavailability Index (BBI), was developed integrating size, polarity, lipophilicity, and molecular shape.
• The predictive performance of BBI was evaluated against traditional physicochemical properties and in vitro cell permeability assays using a dataset of LDDs.

Main Results:

• The Bifunctional Bioavailability Index (BBI) demonstrated superior ability to differentiate oral bioavailability of LDDs compared to individual parameters like polarity, lipophilicity, or size.
• BBI proved more effective than in vitro cell permeability assays in predicting orally bioavailable LDDs within the dataset.
• The new metric offers improved predictive power for optimizing LDD drug candidates.

Conclusions:

• The Bifunctional Bioavailability Index (BBI) is a valuable computational tool for the rational design and optimization of orally bioavailable LDDs.
• Incorporating molecular shape significantly improves the prediction of oral bioavailability for complex bifunctional degraders.
• BBI facilitates more efficient drug discovery efforts for LDD therapeutics.