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

Autor:	Witek J; Laboratory of Physical Chemistry , ETH Zürich , Vladimir-Prelog-Weg 2 , 8093 Zürich , Switzerland., Wang S; Laboratory of Physical Chemistry , ETH Zürich , Vladimir-Prelog-Weg 2 , 8093 Zürich , Switzerland., Schroeder B; Laboratory of Physical Chemistry , ETH Zürich , Vladimir-Prelog-Weg 2 , 8093 Zürich , Switzerland., Lingwood R; Laboratory of Physical Chemistry , ETH Zürich , Vladimir-Prelog-Weg 2 , 8093 Zürich , Switzerland., Dounas A; Laboratory of Physical Chemistry , ETH Zürich , Vladimir-Prelog-Weg 2 , 8093 Zürich , Switzerland., Roth HJ; Novartis Institutes for BioMedical Research , Novartis Pharma AG, Novartis Campus , 4056 Basel , Switzerland., Fouché M; Novartis Institutes for BioMedical Research , Novartis Pharma AG, Novartis Campus , 4056 Basel , Switzerland., Blatter M; Novartis Institutes for BioMedical Research , Novartis Pharma AG, Novartis Campus , 4056 Basel , Switzerland., Lemke O; Department of Biology, Chemistry, Pharmacy , Freie Universität Berlin , Takustrasse 3 , 14195 Berlin , Germany., Keller B; Department of Biology, Chemistry, Pharmacy , Freie Universität Berlin , Takustrasse 3 , 14195 Berlin , Germany., Riniker S; Department of Biology, Chemistry, Pharmacy , Freie Universität Berlin , Takustrasse 3 , 14195 Berlin , Germany.
Jazyk:	angličtina
Zdroj:	Journal of chemical information and modeling [J Chem Inf Model] 2019 Jan 28; Vol. 59 (1), pp. 294-308. Date of Electronic Publication: 2018 Dec 04.
DOI:	10.1021/acs.jcim.8b00485
Abstrakt:	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 .
Databáze:	MEDLINE
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