Design of Deliverable Macrocycles

May 19, 2016
Session 5 of the 2016 Drug Design and Delivery Symposium

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The growing list of synthetic and natural cyclic peptides that cross biological membranes by passive diffusion provide a testing ground for studying membrane permeability in non-traditional drug scaffolds. Scott Lokey will cover the latest round of studies using a variety of macrocyclic model systems to probe the property space within which drug-like passive membrane permeability can be achieved in traditionally non-druglike scaffolds.

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What You Will Learn

  • The “rules” governing cell permeability in large (MW ~ 1000) macrocycles are beginning to come into focus. I will discuss what we know about the interplay between size and lipophilicity in determining passive permeability in this chemical space.  
  • Relatively complex geometric and conformational effects, which relate to backbone elements such as stereochemistry and N-methylation, are major determinants of passive permeability in cyclic peptides. I will describe a variety of new, cell permeable cyclic peptide scaffolds with novel backbone elements.
  • The impact of side chains on permeability is generally driven by their combined contribution to the overall lipophilicity of the molecule, although I will also describe more subtle effects related to side chain branching and steric shielding.   

The Fine Print

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Scott Lokey
UC Santa Cruz

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