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Conformational Analysis of Rifampicin in Solution
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0001-9882-2018
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0002-4205-6040
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2018 (English)Conference paper, Oral presentation only (Other academic)
Abstract [en]

Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

Place, publisher, year, edition, pages
2018.
National Category
Natural Sciences
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-357667OAI: oai:DiVA.org:uu-357667DiVA, id: diva2:1240008
Conference
International School of Biological Magnetic Resonance
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-22Bibliographically approved

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Wieske, HerminaDanelius, EmmaPeintner, StefanKihlberg, JanErdélyi, Máté
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