Molecular docking of ZSTK474 derivatives as potential PI3K-delta inhibitory agents

Authors

DOI:

https://doi.org/10.15421/081417

Keywords:

molecular docking, binding energy, binding site, inhibitors

Abstract

The phosphatidylinositol 3-kinase delta (PI3Kd) controls a range of cellular processes. Its overexpression is found in many human tumors. PI3Kd inhibitors are potential anticancer agents and anti-inflammatory agents for treatment of rheumatoid arthritis. Derivatives of ZSTK474, an effective inhibitor of PI3Kd, were screened virtually by computational docking for inhibitory activity towards PI3Kd. Some of modeled compounds showed better docking energies than ZSTK474 indicating that the former could be potent enzyme inhibitors. Additional binding energy was provided by extra ligand-protein interactions. Substituents in morpholine and benzimidazole rings cause increase and decrease of ligand-protein binding, respectively. Energetically favorable ZSTK474 derivatives satisfy Lipinski’s Rule of five which testifies to their druglikeness (absorption, distribution, metabolism and excretion) and possible pharmacological activity.

Author Biographies

Liudmyla K. Sviatenko, Oles Honchar Dnipropetrovsk National University, 72, Gagarin Ave., Dnipropetrovsk, 49000

Chemistry Department, Ph.D. in Chemistry, Lecturer

Oksana V. Tereshchenko, Kirovohrad Volodymyr Vynnychenko State Pedagogical University, 1, Shevchenko Str., Kirovohrad, 25006

Chemistry Department, Ph.D. in Chemistry, Lecturer

References

Ghigo, A., Hirsch, E. Isoform selective phosphoinositide 3-kinase gamma and delta inhibitors and their therapeutic potential. Recent Pat. Inflamm. Allergy Drug Discov., 2008,vol. 2, p. 1–10.

Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J., Waterfield, M. D. Synthesis and function of 3-phosphory-lated inositol lipids. Annu. Rev. Biochem., 2001, vol. 70, p. 535–602.

Cantley, L. C. The phosphoinositide 3-kinase pathway. Science, 2002, vol. 296, p. 1655–1657.

Sujobert, P., Bardet, V., Cornillet-Lefebvre, P., Hayflick, J. S., Prie, N., Verdier, F., Vanhaesebroeck, B., Muller, O., Pesce, F., Ifrah, N., Hunault-Berger, M., Berthou, C., Villemagne, B., Jourdan, E., Audhuy, B., Solary, E., Witz, B., Harousseau, J. L., Himberlin, C., Lamy, T., Lioure, B., Cahn, J. Y., Dreyfus, F., Mayeux, P., Lacombe, C., Bouscary, D. Essential role for the p110delta isoform in phosphoinositide3-kinase activation and cell proliferation in acute myeloid leukemia. Blood, 2005, vol. 106, p. 1063–1066.

Sommel, C.,Camps, M., Ji, H. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond. Nat. Rev. Immunol., 2007, vol. 7, p. 191–201.

Park, S. J., Min, K. H., Lee, Y. C. Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma. Respirology, 2008, vol. 13, p. 764–771.

Knight, Z. A., Shokat, K. M. Chemically targeting the PI3K family. Biochem. Soc. Trans., 2007, vol. 35, p. 245–249.

Arcaro, A., Wymann, M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J., 1993, vol. 296, p. 297–301.

Liew, C. Y., Ma, X. H., Yap, C. W. Consensus model for identi-fication of novel PI3K inhibitors in large chemical library. J. Comput. Aided Mol. Des., 2010,vol. 24, p. 131–141.

Frederick, R., Mawson, C., Kendall, J. D., Chaussade, C., Rewcastle, G. W., Shepherd, P. R., Denny, W. A. Phosphoino-sitide-3-kinase (PI3K) inhibitors: Identification of new scaffolds using virtual screening. Bioorg. Med. Chem. Lett., 2009,vol. 19, p. 5842–5847.

Hughes, S. J., Millan, D. S., Kilty, I. C., Lewthwaite, R. A., Mathias, J. P., O’Reilly, M. A., Pannifer, A., Phelan, A., Stuhmeier, F., Baldock, D. A., Brown, D. G. Fragment based discovery of a novel and selective PI3 kinase inhibitor. Bioorg. Med. Chem. Lett., 2011,vol. 21, p. 6586–6590.

Shuttleworth, S. J., Silva, F. A., Cecil, A. R. L., Tomassi, C. D., Hill, T. J., Raynaud, F. I., Clarke, P. A., Workman, P. Progress in the preclinical discovery and clinical development of class i and dual class i/iv phosphoinositide 3-kinase (PI3K) inhibitors. Curr. Med. Chem., 2011, vol. 18,

p. 2686–2714.

Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., Balla, T., Weiss, W. A., Williams, R. L., Shokat, K. M. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell, 2006, vol. 125, p. 733–747.

Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer, 2009, vol. 9, no 8, p. 550–562.

Markman, B., Tao, J. J., Scaltriti, M. PI3K pathway inhibitors: better not left alone. Curr. Pharm. Des.,2013, vol. 19, p. 895–906.

Yaguchi, S., Fukui, Y., Koshimizu, I., Yoshimi, H., Matsuno, T., Gouda, H., Hirono, S., Yamazaki, K., Yamori, T. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J. Natl. Cancer Inst., 2006, vol. 98, p. 545–556.

A service of the U.S. National Institutes of Health. Acessed: http://clinicaltrials.gov.

Baiz, D., Hassan, S., Choi, Y. A., Flores, A., Karpova, Y., Yancey, D., Pullikuth, A., Sui, G., Sadelain, M., Debinski, W., Kulik, G. Combination of the PI3K inhibitor ZSTK474 with a PSMA-targeted immunotoxin accelerates apoptosis and regression of prostate cancer. Neoplasia, 2013, vol. 15, p. 1172–1183.

Dan, S., Okamura, M., Mukai, Y., Yoshimi, H., Inoue, Y., Hanyu, A., Sakaue-Sawano, A., Imamura, T., Miyawaki, A., Yamori, T. ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo. Eur. J. Cancer, 2012, vol. 48, no 6, p. 936–943.

Zhao, W., Guo, W., Zhou, Q., Ma, S., Wang, R., Qiu, Y., Jin, M., Duan, H., Kong, D. In Vitro Antimetastatic Effect of phosphatidylinositol 3-kinase inhibitor ZSTK474 on prostate cancer PC3 cells. Int. J. Mol. Sci., 2013, vol. 14, no 7, p. 13577–13591.

Berndt, A., Miller, S., Williams, O., Le, D. D., Houseman, B. T., Pacold, J. I., Gorrec, F., Hon, W., Ren, P., Liu, Y., Rommel, C., Gaillard, P., Ruckle, T., Schwarz, M. K., Shokat, K. M., Shaw, J. P., Williams, R. L. The p110-delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol., 2010, vol. 6, no 2, p. 117–124.

Frisch, M. J., Trucks, G. W., Schlegel, H. B. et al., Gaussian 09, Revision A.02, Gaussian, Inc.: Wallingford CT, 2009.

Trott, O., Olson, A. J. AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem., 2010, vol. 31, p. 455–461.

The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC.

Tetko, I. V., Gasteiger, J., Todeschini, R., Mauri, A., Livingstone, D., Ertl, P., Palyulin, V. A., Radchenko, E. V., Zefirov, N. S., Makarenko, A. S., Tanchuk, V. Y., Prokopenko, V. V. Virtual computational chemistry laboratory – design and description. J. Comput. Aid. Mol. Des., 2005, vol. 19, p. 453–463.

Rewcastle, G. W., Gamage, S. A., Flanagan, J. U., Kendall, J. D., Denny, W. A., Baguley, B. C., Buchanan, C. M., Chao, M., Kestell, P., Kolekar, S., Lee, W., Lill, C. L., Malik, A., Singh, R., Jamieson, S. M. F., Shepherd, P. R. Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]- 1H-benzimidazole (ZSTK474). Eur. J. Med. Chem., 2013, vol. 64, p. 137–147.

Downloads

Published

2014-12-11

Issue

Vol. 22 No. 2 (2014): Bulletin of Dnipropetrovsk University. Series Chemistry

Section

Organic Chemistry

License

Copyright (c) 2014 Oles Honchar Dnipropetrovsk National University

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

  1. Authors reserve the right of attribution for the submitted manuscript, while transferring to the Journal the right to publish the article under the Creative Commons Attribution License. This license allows free distribution of the published work under the condition of proper attribution of the original authors and the initial publication source (i.e. the Journal)
  2. Authors have the right to enter into separate agreements for additional non-exclusive distribution of the work in the form it was published in the Journal (such as publishing the article on the institutional website or as a part of a monograph), provided the original publication in this Journal is properly referenced
  3. The Journal allows and encourages online publication of the manuscripts (such as on personal web pages), even when such a manuscript is still under editorial consideration, since it allows for a productive scientific discussion and better citation dynamics (see The Effect of Open Access).