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A Structure-Derived Compositional Framework for Interpreting Membrane Permeability via Relative Interaction Balance
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DOI：10.1016/j.ejps.2026.107574.png)
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Abstract
En 中文
Membrane permeability is a central determinant of oral drug absorption and underpins the Biopharmaceutics Classification System (BCS), yet its physicochemical interpretation remains challenging when described using conventional structure-based descriptors alone. Although parameters such as lipophilicity and polar surface area capture broad physicochemical tendencies, compounds with similar descriptor values may still exhibit differing permeability-related behavior. Here, commonly used physicochemical descriptors were reorganized into a unified multidimensional representation derived solely from molecular structure, without the use of experimental permeability or solubility data. Within this representation, compounds exhibit a continuous spatial organization in which permeability-related characteristics emerge as relationships among the relative contributions of dispersive, polar, and hydrogen-bonding interactions. Across chemically diverse compounds, those associated with similar BCS classifications tend to occupy overlapping but non-random regions, while compounds with ambiguous or variable classifications are frequently located near transitional areas of the distribution. In particular, compounds associated with BCS Classes II and IV, which often overlap substantially in conventional logP–PSA projections, exhibit differing positional tendencies within the present representation while still maintaining considerable overlap. These observations support the view that permeability-related behavior may be more appropriately interpreted as a continuum of interaction balances rather than as discrete physicochemical categories. The resulting framework provides a structure-derived physicochemical context for comparatively organizing compounds within permeability-related chemical space and may offer a complementary qualitative perspective for interpreting permeability-associated variability in drug discovery and biopharmaceutical evaluation. Importantly, the framework is not intended as a classification or predictive model, but rather as an interpretive representation for contextualizing permeability-related physicochemical relationships. The observed organization is evaluated in relation to externally established classification systems rather than being derived from or optimized against them.
Keywords:
Membrane permeability
Biopharmaceutics Classification System
Hansen solubility parameters
Physicochemical descriptors
Drug absorption
Structure–property relationships
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