Effect of Flexibility, Lipophilicity, and the Location of Polar Residues on the Passive Membrane Permeability of a Series of Cyclic Decapeptides

Cyclic peptides have
received increasing attention over the recent
years as potential therapeutics for “undruggable” targets.
One major obstacle is, however, their often relatively poor bioavailability.
Here, we investigate the structure–permeability relationship
of 24 cyclic decapeptides that share the same backbone N-methylation
pattern but differ in their side chains. The peptides cover a large
range of values for passive membrane permeability as well as lipophilicity
and solubility. To rationalize the observed differences in permeability,
we extracted for each peptide the population of the membrane-permeable
conformation in water from extensive explicit-solvent molecular dynamics
simulations and used this as a metric for conformational rigidity
or “prefolding.” The insights from the simulations together
with lipophilicity measurements highlight the intricate interplay
between polarity/lipophilicity and flexibility/rigidity and the possible
compensating effects on permeability. The findings allow us to better
understand the structure–permeability relationship of cyclic
peptides and extract general guiding principles.