Impact of Halogen Anisotropy on the Membrane Permeability of Halogenated Drugs

Abstract Membrane permeability is central to drug absorption and intracellular target engagement, but the contribution of specific noncovalent interactions to passive permeation remains difficult to quantify. While hydrogen bonds (HBs) are known to influence membrane crossing, the role of halogen bonds (XBs) is still poorly understood. Here, we investigate whether halogen anisotropy influences passive membrane permeation by comparing molecular dynamics simulations performed with and without explicitly emulating the σ-hole via an extra point of charge for two activated XB probes and six halogenated drugs. The resulting computational protocol was generally consistent with the available experimental Caco-2 permeability trends, thereby allowing us to assess the contribution of halogen anisotropy to membrane permeability. Our results suggest that halogen anisotropy might have a measurable role in membrane permeability, primarily for strong XB donors such as iodinated compounds, reflecting a delicate balance between membrane recognition, desolvation, and hydrophobic partitioning.