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

Abstract

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.

Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

“…The implementation of the concept of static and dynamic IMHB in drug discovery programs is also supported by the results obtained by Rossi Sebastiano et al who 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. In this study, the authors firstly collected the available crystal structures for the investigated dataset and showed that all compounds populated multiple distinct conformations.…”

“…Formation of IMHBs within the macrocycle core can thus be expected to be rare, but notable exceptions are found, for instance, in a derivative of bryostatin 2 (Figure A) . However, substituents and coupling groups that connect to the macrocyclic ring can be expected to participate more frequently in IMHB formation . The ansamycin antibiotic rifampicin, which is absorbed in the intestine, provides an example of formation of IMHBs outside the macrocyclic core, as revealed by X‐ray crystallography (Figure B).…”

Prediction of Passive Membrane Permeability by Semi‐Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion

“…Before the validation of the prediction models, we examined the conformer generation. [18][19][20][21][22]25] Thus, we ap- We applied Models A and B to the ensemble of conformers by restricting the maximum number of generated conformers up to 300. The conformer generation represented the solute-size change in water and in membrane.…”

“…[18][19][20][21][22] Many studies have challenged this problem by using QSPR models and have successfully predicted membrane permeability, including that of middle molecules. [18][19][20][21][22] Many studies have challenged this problem by using QSPR models and have successfully predicted membrane permeability, including that of middle molecules.…”

Neue Methoden und Designprinzipien für zellgängige Peptide

“…Chloralkane sind jedoch kleiner und weniger hydrophob als Fluoreszenzfarbstoffeoder Steroide und kçnnen einfach an Peptide und andere Biomoleküle angebunden werden. [83] In den kommenden Jahren kçnnten solche rotierbaren Bindungen als spezifisches Strukturelement zur Maximierung der Zellpenetration etabliert werden. [112,174] [58,177,178] Diese CPPs haben physikochemische Eigenschaften, die denen vieler nicht-zellgängiger Peptide ähnlich sind, und sie passen nicht im eigentlichen Sinne zu einer der drei hier beschriebenen Strategien.…”