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

Matteo Rossi Sebastiano, Bradley C. Doak, Maria Backlund, Vasanthanathan Poongavanam, Björn Over, Giuseppe Ermondi, Giulia Caron, Pär Matsson, Jan Kihlberg

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)4189-4202
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number9
DOIs
Publication statusPublished - 10 May 2018

Cite this

Rossi Sebastiano, Matteo ; Doak, Bradley C. ; Backlund, Maria ; Poongavanam, Vasanthanathan ; Over, Björn ; Ermondi, Giuseppe ; Caron, Giulia ; Matsson, Pär ; Kihlberg, Jan. / Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs beyond the Rule of 5. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 9. pp. 4189-4202.
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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.",
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Rossi Sebastiano, M, Doak, BC, Backlund, M, Poongavanam, V, Over, B, Ermondi, G, Caron, G, Matsson, P & Kihlberg, J 2018, 'Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs beyond the Rule of 5' Journal of Medicinal Chemistry, vol. 61, no. 9, pp. 4189-4202. https://doi.org/10.1021/acs.jmedchem.8b00347

Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs beyond the Rule of 5. / Rossi Sebastiano, Matteo; Doak, Bradley C.; Backlund, Maria; Poongavanam, Vasanthanathan; Over, Björn; Ermondi, Giuseppe; Caron, Giulia; Matsson, Pär; Kihlberg, Jan.

In: Journal of Medicinal Chemistry, Vol. 61, No. 9, 10.05.2018, p. 4189-4202.

Research output: Contribution to journalArticleResearchpeer-review

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