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 language | English |
|---|---|
| Pages (from-to) | 4189-4202 |
| Number of pages | 14 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 61 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 10 May 2018 |
Cite this
}
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 journal › Article › Research › peer-review
TY - JOUR
T1 - Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs beyond the Rule of 5
AU - Rossi Sebastiano, Matteo
AU - Doak, Bradley C.
AU - Backlund, Maria
AU - Poongavanam, Vasanthanathan
AU - Over, Björn
AU - Ermondi, Giuseppe
AU - Caron, Giulia
AU - Matsson, Pär
AU - Kihlberg, Jan
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046812598&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00347
DO - 10.1021/acs.jmedchem.8b00347
M3 - Article
VL - 61
SP - 4189
EP - 4202
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -