Witek, Jagna, Mühlbauer, Max, Keller, Bettina G., Blatter, Markus, Meissner, Axel, Wagner, Beatrix and Riniker, Sereina (2017) Interconversion Rates Between Conformational States as Rationale for the Membrane Permeability of Cyclosporines. Chemphyschem. ISSN 14394235

Abstract

The natural product cyclosporine A (CsA) is the textbook example for the passive membrane permeability of molecules beyond Lipinski's "rule of five". Despite its size and the polar backbone it is able to permeate membranes. The structure of the derivate cyclosporine E (CsE) differs only in a backbone methylation, but the passive membrane permeability is one order of magnitude lower. Kinetic models of CsA in water and chloroform based on multi-microsecond molecular dynamics (MD) simulations had shown the presence of two "congruent" conformational states, i.e. conformations that are adopted both in the polar and apolar environment, with one of them corresponding to the "closed" conformation of CsA with four intra-molecular hydrogen bonds. Here, we use a combination of NMR measurements and MD-based kinetic models in polar and apolar solvents to rationalize the difference in the membrane permeability of CsE and CsA. The most striking difference is found in the interconversion rates between the conformational states favored in water and in chloroform, which are up to one order of magnitude slower for CsE compared to CsA

Item Type:	Article
Date Deposited:	16 Dec 2017 00:45
Last Modified:	16 Dec 2017 00:45
URI:	https://oak.novartis.com/id/eprint/33233