A new screening tool to determine chameleonic properties of macrocycles

Membrane permeability is one of the major caveats for the broader use of macrocyclic compounds in the drug discovery. Some macrocyclic drugs can increase their membrane permeability through conformational changes triggered by different biological environments, a property referred to as chameleonic ability. In this study, the combined NMR spectroscopy and molecular modelling workflow was developed as a screening tool to identify macrocycles prone to conformational changes induced by complexation with metal ions. Three structurally diverse macrocyclic compounds have been investigated to develop and validate the approach; Cyclosporin A as a reference compound known to possess chameleonic properties, Rifampicin and Fidaxomicin.