Conformational Effects on the Passive Membrane Permeability of Synthetic Macrocycles

Macrocyclic compounds (MCs) can have complex conformational
properties
that affect pharmacologically important behaviors such as membrane
permeability. We measured the passive permeability of 3600 diverse
nonpeptidic MCs and used machine learning to analyze the results.
Incorporating selected properties based on the three-dimensional (3D)
conformation gave models that predicted permeability with Q2 = 0.81. A biased spatial distribution of polar
versus nonpolar regions was particularly important for good permeability,
consistent with a mechanism in which the initial insertion of nonpolar
portions of a MC helps facilitate the subsequent membrane entry of
more polar parts. We also examined effects on permeability of 800
substructural elements by comparing matched molecular pairs. Some
substitutions were invariably beneficial or invariably deleterious
to permeability, while the influence of others was highly contextual.
Overall, the work provides insights into how the permeability of MCs
is influenced by their 3D conformational properties and suggests design
hypotheses for achieving macrocycles with high membrane permeability.