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 = 0.

Defining and navigating macrocycle chemical space.

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 class. Using these features, we performed Principal Component Analysis to map oral and non-oral macrocycle drugs and clinical candidates, and also commercially available synthetic MCs, in structure-property space.