Research topics

Small molecule NMR

Our group’s prime task is to provide NMR service in the institute. Chemical problems ranging from simple molecular structure verification and resonance assignment to determination of positional and conformational isomers are routine. More challenging tasks like analysis of conformational equilibria (estimation of conformational energy barriers) and structure elucidation of compounds of natural origin appear every now and then. All standard 1D and 2D NMR methods are applied, mostly on our 200 MHz and 400 MHz spectrometers, although for special cases the 600 MHz spectrometer can be used.
Selected references:

  1. Lends A., Olszewska E., Belyakov S., Erchak N., Liepinsh E. NMR and Quantum-Chemical Studies of Electrostatically Stabilized 1-(N,N-Substituted-aminiomethyl)spirobi[3-oxo(2,5-dioxa-1-silacyclopentan)]ates (ES-Silanates). Heteroatom Chem. (2014). DOI
  2. Petrova M., Muhamadejev R., Cekavicus B., Vigante B., Plotniece A., Sobolev A., Duburs G., Liepinsh E. Experimental and theoretical studies of bromination of diethyl 2,4,6-Trimethyl-1,4-dihydropyridine-3,5-dicarboxylate. Heteroatom Chem. (2014) 25: 114-126. DOI
  3. Goba I., Liepinsh E. 15N NMR of 1,4-dihydropyridine derivatives. Magn. Reson. Chem. (2013) 51: 391-396. DOI

NMR screening

NMR screening is a new area of interest in the institute and is used within the framework of fragment-based drug discovery to screen fragments for binding to a target protein. For this, we have recently acquired a fragment library of about one thousand compounds (see the physicochemical profile of the library). The goal of these studies is to identify small molecules (fragments of drug-like molecules), which bind optimally to the target protein, and evolve them to lead compounds by growing or linking several of the fragment hits. The typical ligand-based NMR screening experiments include saturation transfer difference (STD), WaterLOGSY and T1rho. The experiments are performed on the 600 MHz spectrometer, which is equipped with a cryoprobe to deliver the highest signal-to-noise ratio, critical in these studies.

Selected references:

  1. Jaudzems K., Kuka J., Gutsaits A., Zinovjevs K., Kalvinsh I., Liepinsh E., Liepinsh E., Dambrova M. Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism. J. Enz. Inhib. Med. Chem. (2009) 24: 1269-1275. DOI

Biomolecular NMR

Our prime interest in biomolecular NMR is characterization of small molecule – protein complexes of biomedical or biological relevance in solution. Determination of the small molecule three-dimensional binding mode is achieved by restrained molecular modeling using experimental NMR restraints. This approach assumes that protein chemical shift assignments and the three-dimensional protein structure are obtained beforehand. A second area of interest is protein NMR structure determination. Protein NMR experiments are performed on the 600 MHz spectrometer.

Selected references:

  1. Jaudzems K., Jia X., Yagi H., Zhulenkovs D., Graham B., Otting G., Liepinsh E. Structural basis for 5′-end-specific recognition of single-stranded DNA by the R3H domain from human Sμbp-2. J. Mol. Biol. (2012) 424: 42-53. DOI
  2. Kronqvist N., Otikovs M., Chmyrov V., Chen G., Andersson M., Nordling K., Landreh M., Sarr M., Jörnvall H., Wennmalm S., Widengren J., Meng Q., Rising A., Otzen D., Knight S.D., Jaudzems K., Johansson J. Sequential pH-driven dimerization and stabilization of the N-terminal domain enables rapid spider silk formation. Nat. Commun. (2014) 5: 3254. DOI
  3. Loscha K.V., Jaudzems K., Ioannou C., Su X.-C., Hill F.R., Otting G., Dixon N.E., Liepinsh E. A novel zinc-binding fold in the helicase interaction domain of the Bacillus subtilis DnaI helicase loader. Nucleic Acids Res. (2009) 37: 2395-2404. DOI (Full text)

Molecular modeling

Recent advances in computer technology and molecular modeling have made it possible to accurately predict the physical, chemical and biological properties of small molecules. One area of our interest in molecular modeling is the prediction of energetically favorable conformations and explanation of chemical and physical properties of synthetic compounds. For this purpose, we use quantum chemical methods (DFT, ab initio, semi-empirical) to theoretically predict molecular potential energy, bond vibrations, molecular geometry, chemical reactivity, NMR chemical shifts and other parameters. Molecular modeling also allows to significantly accelerate drug discovery. We use large-scale molecular docking to virtually screen huge compound databases (such as ZINC, Cambridge) and select potentially active compounds. For detailed protein-small molecule interaction analysis we perform molecular dynamics simulations (using CHARMM, Amber or OPLS force fields). The calculations are done on local CUDA GPU-enabled workstations, as well as on computer clusters in Latvia and abroad.

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