Macrocyclic compounds (MCs) are of growing interest for inhibition of challenging drug targets. We consider afresh what structural and physicochemical features could be relevant to the bioactivity of this compound...

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 Q 2 = 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.

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Brownian dynamics (BD) simulations have been performed to study structure and rheology of particle gels under large shear deformation. The model incorporates soft spherical particles, and reversible flexible bond formation. Two different methods of shear deformation are discussed, namely affine and nonaffine deformation, the second being novel in simulation studies of gels. Also two dynamic descriptions of the model are presented, with and without inertia effects. Nonaffine deformation resulted in a slower increase of the stress at small deformation than affine deformation. At large deformation both models gave similar stress responses, although the inertia model resulted in lower stresses. The particle gels, regardless of the model used, were observed to fracture into lumps that compactified due to local reorganization. A reversible yielding transition, as observed in polymer gels, was not found. Fractal properties of the gels were irreversibly lost at large deformation.

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