2. Academic Validation
  3. Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5

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

  • J Med Chem. 2018 May 10;61(9):4189-4202. doi: 10.1021/acs.jmedchem.8b00347.
Matteo Rossi Sebastiano 1,  Bradley C Doak 2,  Maria Backlund 3,  Vasanthanathan Poongavanam 1,  Björn Over 4,  Giuseppe Ermondi 5,  Giulia Caron 5,  Pär Matsson 6,  Jan Kihlberg 1
Affiliations

Affiliations

  • 1 Department of Chemistry - BMC , Uppsala University , Box 576, SE-751 23 Uppsala , Sweden.
  • 2 Department of Medicinal Chemistry, MIPS , Monash University , 381 Royal Parade , Parkville , Victoria 3052 , Australia.
  • 3 Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), a Node at the Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Pharmacy, BMC , Uppsala University , Box 580, SE-751 23 Uppsala , Sweden.
  • 4 Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit , AstraZeneca R&D Gothenburg , SE-431 83 Mölndal , Sweden.
  • 5 Department of Molecular Biotechnology and Health Sciences , University of Torino , Quarello 15 , 10135 Torino , Italy.
  • 6 Department of Pharmacy, BMC , Uppsala University , Box 580, SE-751 23 Uppsala , Sweden.
PMID: 29608068 DOI: 10.1021/acs.jmedchem.8b00347
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.

Figures
Products