Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

• Published in: Chemistry : a European journal Vol. 26; no. 23; pp. 5231 - 5244
• Main Authors: Danelius, Emma, Poongavanam, Vasanthanathan, Peintner, Stefan, Wieske, Lianne H. E., Erdélyi, Máté, Kihlberg, Jan
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 21-04-2020
• Subjects: antibiotics; Binding; Cell permeability; Chemistry; conformation analysis; Cyclosporins; drug design; Drug development; Drugs; Flexibility; macrocycles; Membrane permeability; NMR spectroscopy; Oral administration; Peptides; Permeability; Polar environments; Protein structure; Rifampin; Roxithromycin; Solubility; Spiramycin; Telithromycin; conformation analysis; NMR spectroscopy; drug design; macrocycles; antibiotics
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201905599

It has been hypothesised that drugs in the chemical space “beyond the rule of 5” (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non‐peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs’ passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.
Molecular chameleons: NMR spectroscopy and computational studies reveal that macrocyclic drugs in the beyond rule of 5 chemical space behave as molecular chameleons. This allows them to adapt to the environment and combine otherwise conflicting properties including aqueous solubility, cell permeability and target binding.