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  • 1.
    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)
  • 2.
    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, 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.

  • 3.
    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).

  • 4.
    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).

  • 5.
    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).

1 - 5 of 5
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