The assessment of sulfonylcalixarene derivatives as inhibitors of protein tyrosine phosphatases
Keywords:sulfonylcalixarene, protein tyrosine phosphatase, inhibition, molecular docking, molecular dynamics
Aim. To compare sulfonylcalixarene derivatives containing ionizable or non-ionizable substituents at the upper rim of the macrocycle as inhibitors of protein tyrosine phosphatase 1B (PTP1B) and other PTPs.
Results and discussion. The properties of sulfonylcalixarene with four phosphonic acid groups introduced at the upper rim were compared with those of the macrocycles containing four non-ionizable tert-butyl or trifluoroacetamide functions. The sulfonylcalixarene tetrakis-methylphosphonic acid was found to inhibit PTP1B with IC50 value in the low-micromolar range without selectivity over other PTPs, such as TC-PTP, MEG1, MEG2, SHP2, and PTPβ. At the same time, modification of sulfonylcalixarene with trifluoroacetamide substituents led to inhibition of PTP1B with IC50 of 1.4 μM and 4- to 28 fold selectivity over the other PTPs. In order to understand the ability of inhibiting PTP1B by sulfonylcalixarene with introduced trifluoroacetamide groups the molecular docking and molecular dynamic simulations were performed. The inhibition mechanism was discussed.
Experimental part. The activities of the test compounds in vitro were examined spectrophotometrically measuring the rate of hydrolysis of p-nitrophenyl phosphate as a substrate of PTPs. The molecular docking was performed by AutoDock Vina.
Conclusions. This study can start an approach to develop new inhibitors of PTPs by variations in the nonionogenic substituents on the upper rim of sulfonylcalixarene scaffold.
Cohen, P. (2000). The regulation of protein function by multisite phosphorylation – a 25 year update. Trends in Biochemical Sciences, 25(12),
Hunter, T. (2000). Signaling—2000 and Beyond. Cell, 100(1), 113–127. https://doi.org/10.1016/s0092-8674(00)81688-8
Zhang, Z.-Y. (2001). Protein tyrosine phosphatases: prospects for therapeutics. Current Opinion in Chemical Biology, 5(4), 416–423. https://
Tonks, N. K. (2013). Protein tyrosine phosphatases - from housekeeping enzymes to master regulators of signal transduction. FEBS Journal,
(2), 346–378. https://doi.org/10.1111/febs.12077
He, R., Yu, Z., Zhang, R., & Zhang, Z. (2014). Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacologica Sinica, 35(10),
Mandolini, L., Ungaro, R. (2000). Calixarenes in Action. World Scientific Pub. Co.
Joseph, R., & Rao, C. P. (2011). Ion and Molecular Recognition by Lower Rim 1,3-Di-conjugates of Calixarene as Receptors. Chemical Reviews,
(8), 4658–4702. https://doi.org/10.1021/cr1004524
Naseer, M. M., Ahmed, M., & Hameed, S. (2017). Functionalized calixarenes as potential therapeutic agents. Chemical Biology & Drug Design,
(2), 243–256. https://doi.org/10.1111/cbdd.12818
Molenveld, P., Engbersen, J. F. J., & Reinhoudt, D. N. (2000). Dinuclear metallo-phosphodiesterase models: application of calixarenes as molecular
scaffolds. Chemical Society Reviews, 29(2), 75–86. https://doi.org/10.1039/a804295k
Casnati, A., Sansone, F., & Ungaro, R. (2003). Peptido- and Glycocalixarenes: Playing with Hydrogen Bonds around Hydrophobic Cavities. Accounts of Chemical Research, 36(4), 246–254. https://doi.org/10.1021/ar0200798
Giuliani, M., Morbioli, I., Sansone, F., & Casnati, A. (2015). Moulding calixarenes for biomacromolecule targeting. Chemical Communications,
(75), 14140–14159. https://doi.org/10.1039/c5cc05204a
Trush, V. V., Cherenok, S. O., Tanchuk, V. Y., Kukhar, V. P., Kalchenko, V. I., & Vovk, A. I. (2013). Calixarene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B. Bioorganic & Medicinal Chemistry Letters, 23(20), 5619–5623. https://doi.org/10.1016/j.bmcl.2013.08.040
Trush, V. V., Kharchenko, S. G., Tanchuk, V. Y., Kalchenko, V. I., & Vovk, A. I. (2015). Phosphonate monoesters on a thiacalixarene framework as potential inhibitors of protein tyrosine phosphatase 1B. Organic & Biomolecular Chemistry, 13(33), 8803–8806. https://doi.org/10.1039/c5ob01247c
Buldenko, V., Kobzar, O., Trush, V., Drapailo, A., … Kalchenko, V. (2017). Sulfonyl-bridged Calixarene as an Inhibitor of Protein Tyrosine Phosphatases.
French-Ukrainian Journal of Chemistry, 5(2), 144–151. https://doi.org/10.17721/fujcv5i2p144-151
Gutsche, C. D. (2008). Calixarenes: an introduction. Royal Society of Chemistry, 10.
Barford, D., Flint, A., & Tonks, N. (1994). Crystal structure of human protein tyrosine phosphatase 1B. Science, 263(5152), 1397–1404. https://
Montalibet, J., Skorey, K., McKay, D., Scapin, G., Asante-Appiah, E., & Kennedy, B. P. (2006). Residues Distant from the Active Site Influence Proteintyrosine Phosphatase 1B Inhibitor Binding. Journal of Biological Chemistry, 281(8), 5258–5266. https://doi.org/10.1074/jbc.m511546200
Kamerlin, S. C. L., Rucker, R., & Boresch, S. (2006). A targeted molecular dynamics study of WPD loop movement in PTP1B. Biochemical and Biophysical
Research Communications, 345(3), 1161–1166. https://doi.org/10.1016/j.bbrc.2006.04.181
Kharchenko, S. G., Drapailo, A. B., Kalchenko, O. I., Yampolska, G. D., Shishkina, S. V., Shishkin, O. V., & Kalchenko, V. I. (2013). Thia- and Sulfonyl-
CalixArene Methylphosphonous Acids: Synthesis, Structure, and Amino Acids Binding. Phosphorus, Sulfur, and Silicon and the Related Elements,
(1-3), 243–248. https://doi.org/10.1080/10426507.2012.741164
Iki, N., Kumagai, H., Morohashi, N., Ejima, K., Hasegawa, M., Miyanari, S., & Miyano, S. (1998). Selective oxidation of thiacalixarenes to the sulfinyl-
and sulfonylcalixarenes and their coordination ability to metal ions. Tetrahedron Letters, 39(41), 7559–7562. https://doi.org/10.1016/
Kumagai, H., Hasegawa, M., Miyanari, S., Sugawa, Y., Sato, Y., Hori, T., … Miyano, S. (1997). Facile synthesis of p-tert-butylthiacalixarene by the
reaction of p-tert-butylphenol with elemental sulfur in the presence of a base. Tetrahedron Letters, 38(22), 3971–3972. https://doi.org/10.1016/
Buldenko, V., Kononets, L., Kobzar, O., Drapailo, A., Vyshnevsky, S., Kalchenko, V., & Vovk, A. (2017). The inhibitory potential of calixarenes against nucleotide pyrophosphatase/phosphodiesterase 1. Žurnal organìčnoï ta farmacevtičnoï hìmìï, 15(4(60)), 41–47. https://doi.org/10.24959/ophcj.17.928
Trott, O., & Olson, A. J. (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization,
and multithreading. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334
Tanchuk, V. Y., Tanin, V. O., & Vovk, A. I. (2012). Classification of Binding Site Conformations of Protein Tyrosine Phosphatase 1B. Chemical Biology
& Drug Design, 80(1), 121–128. https://doi.org/10.1111/j.1747-0285.2012.01370.x
Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor,
visualization, and analysis platform. Journal of Cheminformatics, 4(1), 17. https://doi.org/10.1186/1758-2946-4-17
Phillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., … Schulten, K. (2005). Scalable molecular dynamics with NAMD. Journal of
Computational Chemistry, 26(16), 1781–1802. https://doi.org/10.1002/jcc.20289
Zoete, V., Cuendet, M. A., Grosdidier, A., & Michielin, O. (2011). SwissParam: A fast force field generation tool for small organic molecules. Journal of Computational Chemistry, 32(11), 2359–2368. https://doi.org/10.1002/jcc.21816
Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38.https://doi.
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