Andriy I. Vovk

Inhibition of Yersinia protein tyrosine phosphatase by phosphonate derivatives of calixarenes.

Inhibition of Yersinia protein tyrosine phosphatase by calix[4]arene mono-, bis-, and tetrakis(methylenebisphosphonic) acids as well as calix[4]arene and thiacalix[4]arene tetrakis(methylphosphonic) acids have been investigated. The kinetic studies revealed that some compounds in this class are potent competitive inhibitors of Yersinia PTP with inhibition constants in the low micromolar range. The binding modes of macrocyclic phosphonate derivatives in the enzyme active center have been explained using computational docking approach. The results obtained indicate that calix[4]arenes are promising scaffolds for the development of inhibitors of Yersinia PTP.

Stereoselectivity of binding of α-(N-benzylamino)benzylphosphonic acids to prostatic acid phosphatase

The inhibition effects of enantiomerically pure alpha-(N-benzylamino)benzylphosphonic acids and their derivatives on human prostatic acid phosphatase have been investigated. As expected, (R)-alpha-(N-benzylamino)benzylphosphonic acid demonstrated higher affinity for the enzyme than (S)-enantiomer. At the same time, (1R,2S)-phenyl[(1-phenylethyl)amino]methylphosphonic acid was found to be a significantly weaker inhibitor than its (1S,2R)-analogue. The enantioselectivity has been explained using a molecular modeling approach by computational docking of inhibitors into active center of prostatic acid phosphatase.

Fullerene derivatives as a new class of inhibitors of protein tyrosine phosphatases

In this study, we identified water-soluble C60 and C70 fullerene derivatives as a novel class of protein tyrosine phosphatase inhibitors. The evaluated compounds were found to inhibit CD45, PTP1B, TC-PTP, SHP2, and PTPβ with IC50 values in the low micromolar to high nanomolar range. These results demonstrate a new strategy for designing effective nanoscale protein tyrosine phosphatase inhibitors.

Calix[4]arene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B

Сalix[4]arenes bearing methylenebisphosphonic or hydroxymethylenebisphosphonic acid fragments at the wide rim of the macrocycle were studied as inhibitors of PTP1B. Some of the inhibitors showed IC50 values in the micromolar range and good selectivity in comparison with other protein tyrosine phosphatases such as TC-PTP, PTPβ, LAR, and CD45. Kinetic studies indicated that the calix[4]arene derivatives influence PTP1B activity as slow-binding inhibitors. Based on molecular docking results, the binding modes of the macrocyclic bisphosphonates in the active centre of PTP1B are discussed.

Antioxidant and antiradical activities of resorcinarene tetranitroxides

Resorcinarene oxazines bearing four TEMPO fragments at the wide rim of the macrocycle were prepared through the aminomethylation of resorcinarene octols with 4-amino-TEMPO and formaldehyde. Tetra-TEMPO resorcinarenes are efficient scavengers of 1,1-diphenyl-2-picrylhydrazyl radicals. The model studies revealed that macrocyclic structure and intramolecular hydrogen bonding make considerable contribution to antiradical activity of these compounds. Tetra-TEMPO resorcinarenes show also superoxide dismutase-like activity and efficiently inhibit ABAP-induced peroxidation of linoleic acid.

A New, Improved Hybrid Scoring Function for Molecular Docking and Scoring Based on AutoDock and AutoDock Vina

Automated docking is one of the most important tools for structure‐based drug design that allows prediction of ligand binding poses and also provides an estimate of how well small molecules fit in the binding site of a protein. A new scoring function based on AutoDock and AutoDock Vina has been introduced. The new hybrid scoring function is a linear combination of the two scoring function components derived from a multiple linear regression fitting procedure. The scoring function was built on a training set of 2412 protein–ligand complexes from pdbbind database (www.pdbbind.org.cn, version 2012). A test set of 313 complexes that appeared in the 2013 version was used for validation purposes. The new hybrid scoring function performed better than the original functions, both on training and test sets of protein–ligand complexes, as measured by the non‐parametric Pearson correlation coefficient, R, mean absolute error (MAE), and root‐mean‐square error (RMSE) between the experimental binding affinities and the docking scores. The function also gave one of the best results among more than 20 scoring functions tested on the core set of the pdbbind database. The new AutoDock hybrid scoring function will be implemented in modified version of AutoDock.

Classification of Binding Site Conformations of Protein Tyrosine Phosphatase 1B

Hundred and two binding sites from 91 Protein Data Bank files for protein tyrosine phosphatase 1B with different ligands have been compared. It was found that they can be divided into five clusters. Additional clusters were formed by the unliganded and oxidized enzyme. The centroids of the clusters can be used as starting points for further studies of enzyme‐inhibitor interaction by computer simulations. A special software tool has been created for the investigation of protein tyrosine phosphatase 1B and other enzymes. It performs multiple comparisons of selected parts of Protein Data Bank files, as well as further clustering, and determines mobility of separate residues.

Bio-Relevant Derivatives of Calixarene Phosphonic Acids

The calix[4]arenes functionalized at the macrocyclic upper rim with α-hydroxyphosphonic, α-aminophosphonic or methylnebisphosphonic acid groups were synthesized. The complexes formed between the bio-relevent calix[4]arene derivatives and amino acids or dipeptides as well as inhibition effects of calix[4]arene phosphonic acids on alkyline phosphatases acitiy were studied.

Heterogeneity of thylakoid membranes studied by EPR spin probe

A lipophilic nitroxyl radical, 1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl 1-adamantylacetate, has been applied to EPR spin probe study of chloroplasts and subchloroplast fragments of different types. The latter originate from grana and the grana core regions. The binding of the spin probe to the membranes was revealed by specific changes in a shape of the EPR spectra. A share of membrane-bound spin probe was different for chloroplasts and subchloroplast fragments, as well as its rotational correlation time and apparent enthalpy and entropy activation of nitroxide rotational motion. The binding of the spin probe induced a significant decrease in the amount of the oxidized P700 and changes in the kinetics of its light oxidation and dark recovery. This suggests that one of the sites of nitroxyl radical binding is the nearest surrounding of the pigment-protein complexes of Photosystem I (PSI). Distinctions in mobility of spin probe immobilized by chloroplasts and their fragments can be caused by the different environment of the PSI complexes located in various regions of thylakoid membranes.

An EPR spin probe study of liposomes from sunflower and soybean phospholipids

Abstract Comparative properties of lecithin-based liposomes prepared from the mixed phospholipids of sunflower seeds, soybean and egg yolk were investigated by electron paramagnetic resonance (EPR) spectroscopy. For these investigations, stable nitroxide radicals, 1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl 5,7-dimethyladamantane-1-carboxylate (DMAC-TEMPO), 5-doxylstearic acid (5-DSA) and 16-doxylstearic acid (16-DSA) were used as spin probes. Binding of the spin probes to the liposome membranes resulted in a substantial increase of the apparent rotational diffusion correlation times. The EPR spectra of the incorporated nitroxides underwent temperature-dependent changes. For every spin probe, values of apparent enthalpy and entropy of activation were calculated from the temperature dependence of rotational diffusion correlation times via Arrhenius equation. In case of DMAC-TEMPO, the data point to differences between the phospholipid bilayer of liposomes derived from sunflower and soy lecithin, and some similarity between the sunflower and egg yolk liposomes. Anisotropic hyperfine interaction constants of DMAC-TEMPO and 16-DSA included in the liposomes have been analyzed and attributed to different micropolarity of the surroundings of the spin probes. The kinetics of EPR signal decay of DMAC-TEMPO in the presence of 2,2′-azobis(2-amidinopropane) suggest the better stability of the sunflower liposomes to lipid peroxidation as compared to the liposomes prepared from soy lecithin.