Rationalization of the Membrane Permeability Differences in a Series of Analogue Cyclic Decapeptides

Abstract

Cyclization and selected backbone N-methylations are found to be often necessary but not sufficient conditions for peptidic drugs to have a good bioavailability. Thus, the design of cyclic peptides with good passive membrane permeability and good solubility remains a challenge. The backbone scaffold of a recently published series of cyclic decapeptides with six selected backbone N-methylations was designed to favor the adoption of a closed conformation with β-turns and four transannular hydrogen bonds. Although this conformation was indeed adopted by the peptides as determined by NMR measurements, substantial differences in the membrane permeability were observed. In this work, we aim to rationalize the impact of discrete side chain modifications on membrane permeability for six of these cyclic decapeptides. The thermodynamic and kinetic properties were investigated using molecular dynamics simulations and Markov state modeling in water and chloroform. The study highlights the influence that side-chain modifications can have on the backbone conformation. Peptides with a d-proline in the β-turns were more likely to adopt, even in water, the closed conformation with transannular hydrogen bonds, which facilitates transition through the membrane. The population of the closed conformation in water was found to correlate positively with PAMPA log P e.

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

“…This sequence of events is reversed as the drug moves into the cytosol. Various models have been reported for prediction of the relative permeabilities of small sets of macrocyclic peptides and of other compounds in the bRo5 space . One is based on the proportionality of permeability to the free energy of transferring the lowest energy state of a cyclic peptide in a low dielectric medium (the low‐dielectric conformation, LDC) from water to the membrane interior .…”

Prediction of Passive Membrane Permeability by Semi‐Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion

“…[5] If the membrane permeation is faster than the conformational change of the solute in the membrane, each conformer penetrates the membrane while keeping the 3D structure of each conformer, and the dominant conformer in water could be the main contributor to the permeability (permeability model A in Figure 1A). [5] If the membrane permeation is faster than the conformational change of the solute in the membrane, each conformer penetrates the membrane while keeping the 3D structure of each conformer, and the dominant conformer in water could be the main contributor to the permeability (permeability model A in Figure 1A).…”

“…[4][5][6][7][8][9][10][11][12][13][14][15] In these calculations, MD simulations have been applied to explicit atomic models of membrane molecules with solvent water molecules. [4][5][6][7][8][9][10][11][12][13][14][15] In these calculations, MD simulations have been applied to explicit atomic models of membrane molecules with solvent water molecules.…”

“…Recent advances in molecular dynamics (MD) simulations enable the understanding and evaluation of trans-cellular passive permeability. [4][5][6][7][8][9][10][11][12][13][14][15] In these calculations, MD simulations have been applied to explicit atomic models of membrane molecules with solvent water molecules. Since permeation is a very slow process, biased MD simulations have been popular in this analysis.…”

“…Also, we developed formulas considering the above two cases in which the conformational change occurs faster or slower than the diffusion in the membrane. [5]…”