Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5

Conformational flexibility
has been proposed to significantly affect
drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated
the influence of dynamically exposed polarity on cell permeability
and aqueous solubility for a structurally diverse set of drugs and
clinical candidates far beyond the Ro5, all of which populated multiple
distinct conformations as revealed by X-ray crystallography. Efflux-inhibited
(passive) Caco-2 cell permeability correlated strongly with the compounds’
minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous
solubility depended less on the specific 3D conformation. Inspection
of the crystal structures highlighted flexibly linked aromatic side
chains and dynamically forming intramolecular hydrogen bonds as particularly
effective in providing “chameleonic” properties that
allow compounds to display both high cell permeability and aqueous
solubility. These structural features, in combination with permeability
predictions based on the correlation to solvent-accessible 3D PSA,
should inspire drug design in the challenging chemical space far beyond
the Ro5.