engleski

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. The combination of NMR spectroscopy and molecular modelling proved to be a promising tool for quick assessment of the potential chameleonic behaviour of macrocycles through their complexation with metal ions. Additionally, the results confirmed that ability to form intra-molecular, transannular hydrogen bonds is important prerequisite for induced conformational changes.

Macrocycles ; Conformational analysis ; NMR ; Molecular modelling ; Permeability ; Chameleonic properties

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