Repository: Freie Universität Berlin, Math Department

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

Witek, J. and Wang, S. and Schroeder, B. and Lingwood, R. and Dounas, A. and Roth, H.-J. and Fouché, M. and Blatter, M. and Lemke, O. and Keller, B. and Riniker, S. (2019) Rationalization of the Membrane Permeability Differences in a Series of Analogue Cyclic Decapeptides. J. Chem. Inf. Model., 59 (1). pp. 294-308. ISSN 1549-9596, ESSN: 1549-960X

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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 Pe.

Item Type:Article
Subjects:Biological Sciences > Biology > Cell Biology
ID Code:2379
Deposited By: Silvia Hoemke
Deposited On:29 Oct 2019 17:03
Last Modified:30 Oct 2019 08:22

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