UC Santa Cruz

The conformational hypothesis of membrane permeability hypothesizes that certain macrocyclic scaffolds can exhibit an abnormally high degree of permeability producing a larger logP value than expected due to intramolecular hydrogen bonding which locks the macrocycle into a specific conformation where the hydrophilic functional groups are buried within the molecule causing it to become lipophilic enough to cross the membrane. Exploring this concept in previous work resulted in the synthesis of a 32 membered library of cyclic peptides with the same sequence varying in stereochemistry and N-methylation pattern. From this library two cyclic peptides, compounds 1 and 2 were found to exhibit an abnormally large logP value when assayed using the PAMPA permeability assay. This result lead us to synthesize more of these compounds and subject them to a series of NMR and other analytical experiments to computationally determine these two molecules 3D structure as they exist in chloroform solution, used to mimic the environment of the inside of membrane bilayer. These NMR structures were produced using NOESY derived distance restraints and the molecular modeling program CYANA. These structures provide valuable information about what types of conformational motifs can be used when designing novel therapeutic compounds.