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  • 1.
    Bogaerts, Jonathan
    et al.
    Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
    Atilaw, Yoseph
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Aerts, Roy
    Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Johannessen, Christian
    Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Employing complementary spectroscopies to study the conformations of an epimeric pair of side-chain stapled peptides in aqueous solution2021In: RSC Advances, E-ISSN 2046-2069, Vol. 11, no 7, p. 4200-4208Article in journal (Refereed)
    Abstract [en]

    Understanding the conformational preferences of free ligands in solution is often necessary to rationalize structure–activity relationships in drug discovery. Herein, we examine the conformational behavior of an epimeric pair of side-chain stapled peptides that inhibit the FAD dependent amine oxidase lysine specific demethylase 1 (LSD1). The peptides differ only at a single stereocenter, but display a major difference in binding affinity. Their Raman optical activity (ROA) spectra are most likely dominated by the C-terminus, obscuring the analysis of the epimeric macrocycle. By employing NMR spectroscopy, we show a difference in conformational behavior between the two compounds and that the LSD1 bound conformation of the most potent compound is present to a measurable extent in aqueous solution. In addition, we illustrate that Molecular Dynamics (MD) simulations produce ensembles that include the most important solution conformations, but that it remains problematic to identify relevant conformations with no a priori knowledge from the large conformational pool. Furthermore, this work highlights the importance of understanding the scope and limitations of the available techniques for conducting conformational analyses. It also emphasizes the importance of conformational selection of a flexible ligand in molecular recognition.

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  • 2.
    Danelius, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Wieske, Lianne H. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs2020In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, no 23, p. 5231-5244Article in journal (Refereed)
    Abstract [en]

    It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.

  • 3.
    Grintsevich, Sergey
    et al.
    St Petersburg State Univ, Inst Chem, St Petersburg 199034, Russia..
    Sapegin, Alexander
    St Petersburg State Univ, Inst Chem, St Petersburg 199034, Russia..
    Reutskaya, Elena
    St Petersburg State Univ, Inst Chem, St Petersburg 199034, Russia..
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Krasavin, Mikhail
    St Petersburg State Univ, Inst Chem, St Petersburg 199034, Russia..
    An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene-Fused [1.4]Oxazepines2020In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2020, no 35, p. 5664-5676Article in journal (Refereed)
    Abstract [en]

    A four-step approach to the "hydrated imidazoline ring expansion" (HIRE) is presented. In most cases, the ring expansion was the sole process. However, for the first time, an alternative course of the hydrated imidazoline evolution was discovered which gaveN-aminoethyl derivatives. These can, in principle, be converted into the target HIRE products under sufficiently forcing conditions. The approach offers improved flexibility with respect to the peripheral substituents and is also applicable to the synthesis of eleven-membered lactams. We observed that the latter can exist in two stable isomeric forms due to lactam-amide bond isomerization. The latter finding further demonstrates the value of medium-sized rings as multiple-conformer probes for biological target interrogation.

  • 4.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Characterising Halogen Bonding in a Cooperative Model System2020Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Non-covalent interactions are the main driving factor for secondary structure formation of biomacromolecules and are of enormous importance for the direction of molecular recognition events, for example those of importance for drug discovery. Profound understanding of these interactions is of vital importance to achieve high affinity and selectivity of a ligand to a chosen target. Halogen bonding adds another interaction to the toolbox of non-covalent interactions of biomolecules, currently encompassing hydrogen bonds, van der Waals interactions, π-π interactions and salt bridges. As the halogen bond has similar strength and directionality to the hydrogen bond, it is suitable for implementation into biomolecules and drug candidates. Regardless its potential, examples where intuitive introduction of halogen bonding in protein-like structures was exploited for structure stability, target selectivity or binding enhancement, are scarce. Motivated to make halogen bonds applicable in biomolecules, we designed a β-hairpin forming peptide inheriting a XB interaction site R-I···O-R. High resolution solution NMR spectroscopy provided insights in the dynamic conformational behaviour influenced by an array of interactions directing the structure of flexible molecules in solution. The combination of NOE-based interproton distance analysis and computational investigation demonstrates the capability of conformational stabilisation of a β-hairpin foldamer by a halogen bond. Residual dipolar coupling (RDC) analysis proved that the bond orientations are compatible with a geometry, in which a conformation stabilizing I···O halogen bond is formed. This study demonstrates the use of a cooperatively folding system to detect a weak secondary interaction, a halogen bond, in solution by detecting its influence on the overall folding stability.

  • 5.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Shape Matters: Characterization of Weak Interactions and Macrocycles by Conformational Analysis2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    When studying conformational ensembles, it is most challenging to identify and characterize rapidly interconverting individual conformers. A precise description of the structural dynamics, however, rewards viable knowledge on conformation stabilizing forces as well as on the impact of external influences on the conformer composition. This thesis focusses on the solution NMR spectroscopic conformational analysis of flexible molecules with the aim to unveil the impact, strength and geometry of a single weak non-covalent interaction, a halogen bond. In addition, I investigated the impact of the solvent polarity on the conformational distribution of macrocyclic drugs.

    Weak interactions are difficult to characterize in solution with current techniques. Therefore, I designed a peptidic β-hairpin model system that serves as platform to probe a single weak halogen bond in solution. The presented strategy benefits from the cooperativity of non-covalent forces, from preorganization, and from the entropic advantage of studying an interaction in an intramolecular setting. A weak C−I···O halogen bond was characterized thermodynamically and geometrically using NMR-based variable temperature, NOE, scalar coupling and RDC analyses. Time-averaged NMR parameters were deconvoluted with NAMFIS and by Singular Value Decomposition as implemented into MSpin. Characterization of such a weak interaction (ΔΔG° < 0.9 kJ/mol) in dilute solution is remarkable.

    Making use of NMR-based ensemble analysis, I further studied the impact of solvent polarity on the conformational distribution of macrocyclic drugs that do not obey Lipinski’s Rule-of-5, yet experience good membrane permeability. I demonstrate experimentally that this class of compounds behaves as molecular chameleons by adjusting their conformation to shield or expose polar functionalities as an adaptation to the surrounding environment. Solution ensembles in D2O and CDCl3 mimicking the plasma/cytosol and cell membrane, respectively, were determined and thus revealed that the flexibility of studied macrocycles facilitates a major difference in size and polarity between different environments. 

    Overall, this thesis demonstrates the capabilities and precision of solution NMR spectroscopic conformation analysis techniques, and two possible applications of their use for solving scientific challenges of high relevance to medicinal and organic chemistry.

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  • 6.
    Peintner, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdelyi, Mate
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. The Swedish NMR Centre.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    The Solvent Polarity Dependence of Macrocycles’ Conformations2018Conference paper (Refereed)
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  • 7.
    Peintner, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Pushing the Limits of Characterising a Weak Halogen Bond in Solution2022In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 5, article id e202103559Article in journal (Refereed)
    Abstract [en]

    Detection and characterisation of very weak, non-covalent interactions in solution is inherently challenging. Low affinity, short complex lifetime and a constant battle against entropy brings even the most sensitive spectroscopic methods to their knees. Herein we introduce a strategy for the accurate experimental description of weak chemical forces in solution. Its scope is demonstrated by the detailed geometric and thermodynamic characterisation of the weak halogen bond of a non-fluorinated aryl iodide and an ether oxygen (0.6 kJ mol−1). Our approach makes use of the entropic advantage of studying a weak force intramolecularly, embedded into a cooperatively folding system, and of the combined use of NOE- and RDC-based ensemble analyses to accurately describe the orientation of the donor and acceptor sites. Thermodynamic constants (ΔG, ΔH and ΔS), describing the specific interaction, were derived from variable temperature chemical shift analysis. We present a methodology for the experimental investigation of remarkably weak halogen bonds and other related weak forces in solution, paving the way for their improved understanding and strategic use in chemistry and biology.

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  • 8.
    Poongavanam, Vasanthanathan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Univ Gothenburg, Dept Chem & Mol Biol, Kemivagen 10, SE-41296 Gothenburg, Sweden.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Alcaraz, Lilian
    Johnson & Johnson Innovat, Med Chem, One Chapel Pl, London W1G 0BG, England.
    Caron, Giulia
    Univ Torino, Dept Mol Biotechnol & Hlth Sci, Quarello 15, I-10135 Turin, Italy.
    Cummings, Maxwell D.
    Janssen Res & Dev, 1400 McKean Rd, Spring House, PA 19477 USA.
    Wlodek, Stanislaw
    OpenEye Sci Software, 9 Bisbee Court, Santa Fe, NM 87508 USA.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Swedish NMR Ctr, Medicinaregatan 5, SE-40530 Gothenburg, Sweden.
    Hawkins, Paul C. D.
    OpenEye Sci Software, 9 Bisbee Court, Santa Fe, NM 87508 USA.
    Ermondi, Giuseppe
    Univ Torino, Dept Mol Biotechnol & Hlth Sci, Quarello 15, I-10135 Turin, Italy.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?2018In: ACS Omega, E-ISSN 2470-1343, Vol. 3, no 9, p. 11742-11757Article in journal (Refereed)
    Abstract [en]

    Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conforrriations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of la set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conforinational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.

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  • 9.
    Reutskaya, Elena
    et al.
    Institute of Chemistry, Saint Petersburg State University, Saint Petersburg 199034, Russia.
    Sapegin, Alexander
    Institute of Chemistry, Saint Petersburg State University, Saint Petersburg 199034, Russia.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Krasavin, Mikhail
    Institute of Chemistry, Saint Petersburg State University, Saint Petersburg 199034, Russia.
    Sulfur Oxidation Increases the Rate of HIRE-Type [1.4]Thiazepinone Ring Expansion and Influences the Conformation of a Medium-Sized Heterocyclic Scaffold2021In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 8, p. 5778-5791Article in journal (Refereed)
    Abstract [en]

    The hydrated imidazoline ring expansion (HIRE-type) reaction was investigated for a series of di(hetero)arene-fused [1.4]thiazepinones in comparison with their sulfone counterparts. The sulfones were found to undergo ring expansion at a much higher rate compared to the thioethers, much in line with the current mechanistic understanding of the process. Moreover, the amide bond cis- and trans-isomers of the ring-expanded products were found, in the case of sulfones, to be stabilized through an intramolecular hydrogen bond. The latter phenomenon was studied in detail by NMR experiments and corroborated by X-ray crystallographic information.

  • 10.
    Umereweneza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Department of Chemistry, College of Science and Technology, University of Rwanda, Kigali, Rwanda.
    Atilaw, Yoseph
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Rudenko, Anastasia
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Bourgard, Catarina
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Xiong, Ruisheng
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Muhizi, Théoneste
    Department of Chemistry, College of Science and Technology, University of Rwanda, Kigali, Rwanda.
    Sunnerhagen, Per
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Macrocyclic Pyrrolizidine Alkaloids and Silphiperfolanol Angelate Esters from Solanecio mannii2023In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 26, no 8, article id e202201280Article in journal (Refereed)
    Abstract [en]

    Three new compounds, the silphiperfolanol angelate ester umutagarananol (1), the macrocyclic pyrrolizidine alkaloids umutagarinine A and B (23), and five known secondary metabolites (48) were isolated from the CH2Cl2−MeOH (1 : 1) extract of the roots and the stem bark of Solanecio mannii (Hook. f.) (Asteraceae). The isolated compounds were characterized by NMR and IR spectroscopic, and mass spectrometric analyses, whereas the relative stereochemistry of 4 was established by NAMFIS-based combined computational and solution NMR analysis. Synthetic modification of 5 provided two new compounds, 2-angeloyloxy-4,8-epoxypresilphiperfolane (9) and 2-angeloyloxy-4,8-epoxypresilphi-perfolane (10). The crude extracts and the isolated constituents showed weak antibacterial activities (EC50 0.7–13.3 mM) against the Gram-negative Escherichia coli and the Gram-positive Bacillus subtilis. Compounds 2, 3 and 4 exhibited strong cytotoxicity against MCF-7 human breast cancer cells, with EC50 values of 35.6, 21.7 and 12.5 μM, respectively.

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  • 11.
    Wieske, Hermina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Swedish NMR Centre.
    Conformational Analysis of Rifampicin in Solution2018Conference paper (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).

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  • 12.
    Wieske, Hermina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Swedish NMR Centre.
    Conformational Analysis of Rifampicin in Solution.2018Conference paper (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).

  • 13.
    Wieske, Hermina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Conformational Analysis of Rifampicin in Solution2018Conference paper (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).

  • 14.
    Wieske, Lianne H. E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Ensemble determination by NMR data deconvolution2023In: Nature Reviews Chemistry, E-ISSN 2397-3358, Vol. 7, p. 511-524Article, review/survey (Refereed)
    Abstract [en]

    Nuclear magnetic resonance (NMR) is the spectroscopic technique of choice for determining molecular conformations in solution at atomic resolution. As solution NMR spectra are rich in structural and dynamic information, the way in which the data should be acquired and handled to deliver accurate ensembles is not trivial. This Review provides a guide to the NMR experiment selection and parametrization process, the generation of viable theoretical conformer pools and the deconvolution of time-averaged NMR data into a conformer ensemble that accurately represents a flexible molecule in solution. In addition to reviewing the key elements of solution ensemble determination of flexible mid-sized molecules, the feasibility and pitfalls of data deconvolution are discussed with a comparison of the performance of representative algorithms.

  • 15.
    Yang, Jie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Talibov, Vladimir O
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Uppsala Univ, Dept Chem BMC, SE-75123 Uppsala, Sweden.
    Rhee, Claire
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Geitmann, Matthis
    Beactica AB, SE-75450 Uppsala, Sweden.
    Sebastiano, Matteo Rossi
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Simon, Bernd
    EMBL Heidelberg, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
    Hennig, Janosch
    EMBL Heidelberg, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany.
    Dobritzsch, Doreen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD12020In: ACS Omega, E-ISSN 2470-1343, Vol. 5, no 8, p. 3979-3995Article in journal (Refereed)
    Abstract [en]

    Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme which regulates the methylation of Lys4 of histone 3 (H3) and is overexpressed in certain cancers. We used structures of H3 substrate analogues bound to LSD1 to design macrocyclic peptide inhibitors of LSD1. A linear, Lys4 to Met-substituted, 11-mer (4) was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent K-i = 2.3 mu M) than 4. Linear and macrocyclic peptides exhibited unexpected differences in structure-activity relationships for interactions with LSD1, indicating that they bind LSD1 differently. This was confirmed by the crystal structure of 31 in complex with LSD1-CoREST1, which revealed a novel binding mode at the outer rim of the LSD1 active site and without a direct interaction with FAD. NMR spectroscopy of 31 suggests that macrocyclization restricts its solution ensemble to conformations that include the one in the crystalline complex. Our results provide a solid basis for the design of optimized reversible LSD1 inhibitors.

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