Tag Archives: computer simulation
Thiacalix[4]arene С-1193 – a promising inhibitor of the sodium pump in the uterine smooth muscle cells
O. V. Maliuk1*, T. O. Veklich1, O. V. Tsymbalyuk2, O. V. Bevza1,
S. O. Cherenok3, A. I. Selikhova3, V. I. Kalchenko3, S. O. Kosterin1
1Palladin Institute of Biochemistry, National Academy of Sciences
of Ukraine, Kyiv, Ukraine;
*e-mail: sanya2000ua@gmail.com;
2Educational and Scientific Institute of High Technologies,
Taras Shevchenko National University of Kyiv, Kyiv, Ukraine;
3Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
Received: 29 May 2025; Revised: 18 July 2025;
Accepted: 12 September 2025; Available on-line: 17 September2025
Thiacalix[4]arene C-1193 (25,27-dibutoxythiacalix[4]arene-bis-hydroxymethylphosphonic acid) was shown to inhibit the activity of Na+,K+-ATPase with a high efficiency (І0.5 = 42.1 ± 0.6 nM) with no effect on the activity of Mg2+-ATPase, Са2+-ATPase and Са2+,Mg2+-ATPase in the plasma membrane fraction of rat uterine smooth muscle cells. The kinetic regularities of the C-1193 inhibitory effect on Na+,K+-ATPase activity were investigated. It was demonstrated that C-1193 increased the enzyme activation constant by Na+ but not by K+ ions. The contractile activity of the rat uterine horns was investigated by tenzometric methods with the use of longitudinal uterine smooth muscle strips with intact endometrium. С-1193 induced a considerable increase in the amplitude of the acetylcholine-induced contractions as well as the maximal velocity of the contraction and relaxation phases. No effect of С-1193 on contractive activity induced by the selective agonist of М3-cholinoreceptors cevimeline was observed. The results of computer simulation showed that С-1193inhibitory effect must be related to the cooperative action of methylene bisphosphonate fragments on the upper rim of the calixarene platform, and the linker sulfur atoms of calixarene “cup” on the Na+,K+-ATPase macrostructure.
Kinetic regularities of thiacalix[4]arene C-1087 inhibitory effect on the activity of Mg(2+)-dependent Ca(2+)-transporting ATP hydrolase in the plasma membrane of smooth muscle cells
Т. О. Veklich1, О. V. Bevza1, О. V. Maliuk1*, S. О. Kosterin1,
R. V. Rodik2, S. H. Vyshnevskyi2, V. І. Kalchenko2
1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
*e-mail: alexmaliukid@gmail.com;
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine
Received: 05 November 2023; Revised: 04 January 2024;
Accepted: 01 February 2024; Available on-line: 26 February 2024
The experiments with the suspension of plasma membranes of myometrium cells, treated with 0.1% digitonin solution, were used to study kinetic regularities of the inhibitory effect of tetra-N-phenylsulfonyl trifluoroacetamidine-thiacalixarene (С-1087) on the activity of Са2+,Mg2+-ATPase. The studies demonstrated the impact of C-1087 on the cumulative effect and the maximal velocity of ATP hydrolysis. No effect of С-1087 on the affinity between Са2+,Mg2+-ATPase, and АТР, affinity and cumulative effect of Ca ions and activation coefficient for Mg ions was revealed. A considerable decrease in the maximal velocity of ATP hydrolysis evidenced a complete non-competitive mechanism of inhibiting Са2+,Mg2+-АТРase activity with thiacalix[4]arene С-1087. Computer simulation demonstrated that thiacalix[4]arene С-1087 inhibiting effect on Са2+,Mg2+-ATPase may be conditioned by the cumulative effect of four spatially oriented N-sulfonylamidine groups on the upper rim of its macrocyclic platform.
The сalix[4]arene C-107 is highly effective supramolecular inhibitor of the Na+,K+-АТРase of plasmatic membrane
O. V. Bevza1, T. O. Veklich1, O. A. Shkrabak1, R. V. Rodik2, V. I. Kalchenko2, S. O. Kosterin1
1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: kinet@biochem.kiev.ua;
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: vik@bpci.kiev.ua
The inhibition of the Na+,K+-АТРase activity of the myometrium cell plasma membranes with calixarene С-107 (5,17-diamino(2-pyridyl)methylphosphono-11,23-di-tret-butyl-26,28-dihydroxy-25,27-dipropoxycalix[4]arene) was investigated. It has been shown that calixarene С-107 reduced the Na+,K+-АТРase activity more efficiently than ouabain did, while it did not practically influence the “basal” Mg2+-АТРase activity of the same membrane. The magnitude of the cofficient of inhibition I0.5 was 33 ± 4 nМ, Hill coefficient was 0.38 ± 0.06. The model calixarene C-150 – the calixarene “scaffold” (26,28-dihydroxy-25,27-dipropoxycalix[4]arene), and the model compound М-3 (4-hydroxyaniline(2-pyridine)methylphosphonic acid) – a fragment of the calixarene С-107, had practically no influence on the enzymatic activity of Na+,K+-АТРase and Mg2+-АТРаse. We carried out the computer simulation of interaction of calixarenes C-107 and the mentioned model compound with ligand binding sites of the Na+,K+-АТРase of plasma membrane and structure foundation of their intermolecular interaction was found out. The participation of hydrogen, hydrophobic, electrostatic and π-π (stacking) interaction between calixarene and enzyme aminoacid residues, some of which are located near the active center of Na+,K+-АТРase, was discussed.