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Chemical Structure of Lipid A: Recent Advances in Structural Analysis of Biologically Active Molecules
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Ulrich Zähringer, Buko Lindner, Ernst T. Rietschel
With the introduction of complex solvent systems, native and underivatized lipids such as PE, PS, and gangliosides and also underivatized lipid A became accessible to NMR spectroscopy (112,131). With such solvents it was possible to analyze mono- and bisphosphorylated lipid A without further derivatization, leaving the possibility of recording even long-range heteronuclear couplings, which is useful not only for the study of primary lipid A structures, but also for conformational analysis. Nuclear Overhauser effect (NOE) measurements by two-dimensional spectroscopy (NOESY) have gained special interest with respect to conformational analysis. They became available for underivatized lipid A due to the quality of signal resolution in the above-mentioned solvent system. In this way, data on the conformation(s) of lipid A molecules in solution could be obtained (see below) (131).
Chemical Exchange Saturation Transfer and Amide Proton Transfer Imaging
Published in Shoogo Ueno, Bioimaging, 2020
The Z-spectrum not only consists of direct saturation and the CEST (APT) effect but also includes signal reductions by the non-specific magnetization transfer (MT) effect and the nuclear Overhauser effect (NOE) (Figure 5.3). The non-specific MT effect represents saturation transfer via complex mechanisms involving cross-relaxation [18] and chemical exchange [19]. In contrast to CEST, which is based on saturation transfer through proton exchange (chemical exchange) between water and mobile structures with long T2, non-specific MT occurs between semisolid macromolecules with short T2, such as myelin and water. The NOE is another saturation transfer mechanism that is observed upfield from the water frequency [20].
Three-Dimensional Structures of the Chemokine Family
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Wayne J. Fairbrother, Nicholas J. Skelton
The dispersion of aliphatic proton resonances (particularly those of methyl groups) in the NMR spectrum of MGSA is relatively poor, due mainly to the lack of aromatic residues in the polypeptide sequence.13 Some differences observed between the two structures, particularly in the N-loop region, may therefore be due to errors in the assignment of NOE cross peaks in homonuclear NOESY spectra; such errors are more easily avoided when using three-dimensional heteronuclear-edited NMR spectra, because the proton resonances are further dispersed by the chemical shifts of their directly attached heteronuclei (15N or 13C). In addition, the RMS deviations from the experimental restraints reported for the heteronuclear-derived structure are significantly lower than those reported for the homonuclear-derived structure (0.009 ± 0.001 and 0.080 ± 0.001 Å, respectively, for the experimental distance restraints and 0.068 ± 0.014 and 1.63 ± 0.16°, respectively, for the experimental dihedral restraints), indicating that fewer inconsistencies exist between the heteronuclear-derived structure and the experimental data. For these reasons, the following discussion focuses mainly upon the heteronuclear-derived MGSA structure. However, most of the conclusions derived from analysis of this structure also apply to the homonuclear-derived MGSA structure.
Synthesis, biological evaluation and theoretical studies of (E)-1-(4-sulfamoyl-phenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones as human carbonic anhydrase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Farhat Ramzan, Syed Ayaz Nabi, Mehak Saba Lone, Alessandro Bonardi, Aabid Hamid, Sameena Bano, Kalicharan Sharma, Syed Shafi, Mohammed Samim, Kalim Javed, Claudiu T. Supuran
The current research is an expansion of our ongoing initiative12,30–33 to create potentially and biologically active drugs by adopting a hybrid pharmacophore strategy. Designing and synthesising of hybrid molecules were achieved by joining the pyrrolone ring through two methylene groups with benzene sulphonamide. Here, we present the synthesis and inhibitory profile of twenty novel (E)-1–(4-sulfamoylphenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones (3a-t) against two cystosolic (hCA I and II) and two membrane bound, tumour-related hCA IX and XII isoforms. The exocyclic double bond in the target compounds (3a–t) allows for the possibility of either E or Z-isomers. The (E)-configuration appears to be suggested by calculations of δ values using incremental parameters for the hydrogen (semicyclic double bond). This is consistent with the results that have previously been reported14. A nuclear overhauser effect (NOE) experiment was carried to analyse the compound 3k in order to ascertain the geometry of the target compounds. The interaction between an olefinic proton and H-4 on the pyrrolone ring would be clearly visible through NOE analysis if 3k is the Z isomer. The fact that an olefinic proton did not engage in interaction with H-4 on the pyrrolone ring suggests the E form (Figure S1 and S2). The outcome of the inhibitory efficacy of such sulphonamide derivatives displayed good results and further strengthened the significance of the sulphonamides in the medicinal chemistry field of CAIs.
Characterization of co-amorphous carvedilol–maleic acid system prepared by solvent evaporation
Published in Pharmaceutical Development and Technology, 2023
Takayuki Furuishi, Nanami Sato-Hata, Kaori Fukuzawa, Etsuo Yonemochi
The nuclear overhauser effect (NOE) arises from interactions between atoms located within 4–5 Å in a molecule. In simple terms, the intensity of a given NMR resonance can be affected by nearby irradiating atoms; in small molecules (less than 1000 Daltons), the effect is to increase the magnitude of the peak. NOESY is a 2D experiment that reveals all such NOE contacts within a molecule and can be very useful in structural assignment. It does have some drawbacks, such as long acquisition times and occasional difficulties in discriminating noise from peaks. An alternative is to use a 1D pulse sequence, known as an NOE difference experiment. In this method, a specific resonance is irradiated and then the resulting proton spectrum is recorded. The difference element arises from subtraction of the normal (i.e. no NOE) experiment from the enhanced spectrum. If the experiment has been well set-up, the only peaks remaining will be those that have been enhanced by the NOE effect, and the irradiated peak will be seen as a very large negative. Therefore, to investigate the interaction site in detail, we measured the NOE difference spectra.
Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies
Published in Expert Opinion on Drug Discovery, 2023
Typically, the 2D-NOESY spectra, focusing on the imino proton region, are first measured and the signals are assigned to determine the secondary structure [171]. Then, NMR measurements (2D-NOESY or 2D 1H-1H TOCSY) for the non-exchangeable protons are performed, and the NOE cross-peaks between purine H2 (only adenine), H8, or pyrimidine H6 and pyrimidine H5 or ribose H1’ are assigned. Following signal assignment, structural information (proton–proton distance, dihedral angle, and base pairing) is derived, and a restraint file is created for structure calculations. Currently, most calculations are performed using the simulated annealing protocol, and the calculations are performed until the restraints are satisfied and the structure converges. Iterative rounds of signal assignment and structure calculations are made until an acceptable ensemble of structures is obtained.