Specific inhibitors of urokinase plasminogen activator for treatment of cancers; In silico approach
DOI:
https://doi.org/10.46570/utjms.vol7-2020-346Keywords:
Urokinase, Tissue Plasminogen Activator, Inhibitor, Molecular ModelingAbstract
Invasion, metastasis and angiogenesis are fundamental processes in the development of solid cancers. All these depend on the proteolysis where plasminogen activation system (PAS) is the prominent component. Plasmin of PAS, with a broad spectrum of proteins lysed, is secreted as a pro-enzyme and then activated by urokinase (uPA) or tissue plasminogen activator (tPA). Urokinase is in control of pericellular proteolysis while tPA mediates intravascular fibrinolysis. The most effective way to reduce excessive activity of plasmin in cancers is by inactivation of its activators (PAs). Inhibition of PAs reduces tumor size of cancers in vivo. However, for successful targeted anticancer therapy it is essential to find specific uPA inhibitors and to protect normal function of tPA. Unfortunately, most known inhibitors are unspecific, acting on both PAs. PAs are highly homologous enzymes with extreme similarities in their active sites so large numbers of chemicals need to be tested to find novel specific uPA inhibitors.
Methods:
As the availability of 3D protein structures determined experimentally by X-ray crystallography is growing, computational methods are ever more used in targeted drug discovery. AutoDock Vina molecular docking, exploring binding of small molecules to target protein using a Monte Carlo technique and scoring function, is gaining popularity due to its excellent prediction accuracy.
Results:
Using AutoDock we have found many inhibitors of PA from our 3D database of 6170 compounds which bind in silico to X-ray structures of the specificity pocket (B187-B197, B212-B229) of both PAs preventing activation of plasminogen. However we were successful in identifying a few molecules which are specific for uPA. For example: both amiloride and chrysin bind to the specificity pocket of uPA but not to tPA. We have found that they bind to other parts of tPA, distant from the specificity pocket, thus preserving the tPA enzymatic activity while being effective toward uPA.
Conclusion: In silico search yield specific inhibitors of uPA which, when verified for safety and efficiency by in vivo testing, could be used as novel therapeutics to limit metastasis and angiogenesis in anticancer therapy.
References
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6. Buckley BJ, Kelso MJ, Ali U, and Ranson M (2018) The Urokinase Plasminogen Activation System in Rheumatoid Arthritis: Pathophysiological Roles and Prospective Therapeutic Targets. Curr Drug Targets.
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10. Jeanneret V and Yepes M (2016) The Plasminogen Activation System Promotes Dendritic Spine Recovery and Improvement in Neurological Function After an Ischemic Stroke. Transl Stroke Res.
11. Liu YX (2004) Plasminogen activator/plasminogen activator inhibitors in ovarian physiology. Front Biosci 9:3356-3373.
12. Shahrour K, Keck R, and Jankun J (2015) Application of long-acting VLHL PAI-1 379 during sutureless partial nephrectomy in mice reduces bleeding. Biomed Res Int 2015:392862.
13. Li Y and Cozzi PJ (2007) Targeting uPA/uPAR in prostate cancer. Cancer Treat Rev 33(6):521-527.
14. McMahon BJ and Kwaan HC (2015) Components of the Plasminogen-Plasmin System as Biologic Markers for Cancer. Adv Exp Med Biol 867:145-156.
15. Rabbani SA and Xing RH (1998) Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. Int J Oncol 12(4):911-920.
16. Akudugu J, Serafin A, and Bohm L (2015) Further evaluation of uPA and PAI-1 as biomarkers for prostatic diseases. J Cancer Res Clin Oncol 141(4):627-631.
17. LeBeau AM, et al. (2015) Imaging active urokinase plasminogen activator in prostate cancer. Cancer Res 75(7):1225-1235.
18. Skovgaard D, Persson M, and Kjaer A (2017) Imaging of Prostate Cancer Using Urokinase-Type Plasminogen Activator Receptor PET. PET Clin 12(2):243-255.
19. Bode W and Renatus M (1997) Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function.Curr Opin Struct Biol 7(6):865-872.
20. Lamba D, et al. (1996) The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator. J Mol Biol 399 258(1):117-135.
21. Lin Z, et al. (2011) Structural basis for recognition of urokinase-type plasminogen activator by plasminogen activator inhibitor-1. J Biol Chem 286(9):7027-7032.
22. Spraggon G, et al. (1995) The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure 3(7):681-691.
23. Takehara S, et al. (2009) The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability. J Mol Biol 388(1):11-20.
24. Bhongade BA, Gouripur VV, and Gadad AK (2005) 3D-QSAR CoMFA studies on trypsin-like serine protease inhibitors: a comparative selectivity analysis. Bioorg Med Chem 13(8):2773-2782.
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27. Zhang D, et al. (2017) Role of Vascular Endothelial Cells in Disseminated Intravascular Coagulation Induced by Seawater Immersion in a Rat Trauma Model. Biomed Res Int 2017:5147532.
28. Bello M (2018) Advances in Theoretical Studies on the Design of Single Boron Atom Compounds. Curr Pharm Des 24(29):3466-3475.
29. Gns HS, Gr S, Murahari M, and Krishnamurthy M (2019) An update on Drug Repurposing: Re-written saga of the drug’s fate. Biomed Pharmacother 110:700-716.
30. Hoi PM, et al. (2015) Recent advances in structure-based drug design and virtual screening of VEGFR tyrosine kinase inhibitors. Methods 71:85-91.
31. Tamay-Cach F, et al. (2016) In Silico Studies Most Employed in the Discovery of New Antimicrobial Agents. Curr Med Chem 23(29):3360-3373.
32. Wang SH and Yu J (2018) Structure-based design for binding peptides in anticancer therapy. Biomaterials 156:1-15.
33. Daniyan MO and Ojo OT (2019) In silico identification and evaluation of potential interaction of Azadirachta indica phytochemicals with Plasmodium falciparum heat shock protein 90. J Mol Graph Model 87:144-164.
34. Foroughi K, Khaksari M, and Shayannia A (2018) Molecular Docking Studies of Methamphetamine and Amphetamine-Related Derivatives as an Inhibitor against dopamine Receptor. Curr Comput Aided Drug Des.
35. Kumar S, Khatik GL, and Mittal A (2018) In-silico Molecular Docking Study to Search New SGLT2 Inhibitor based on Dioxabicyclo[3.2.1] octane Scaffold. Curr Comput Aided Drug Des.
36. Sadati SM, Gheibi N, Ranjbar S, and Hashemzadeh MS (2019) Docking study of flavonoid derivatives as potent inhibitors of influenza H1N1 virus neuraminidase. Biomed Rep 10(1):33-38.
37. Sepehri B, Rezaei M, and Ghavami R (2018) The in silico identification of potent anti-cancer agents by targeting the ATP binding site of the N-domain of HSP90. SAR QSAR Environ Res 29(7):551-565.
38. Trott O and Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455-461.
39. Kang YN, Stuckey, J.A., Nienaber, V., Giranda, V. (2012) Crystal Structure of the Urokinase. To be published.
40. Zeslawska E, et al. (2000) Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design. Journal of molecular biology 301(2):465-475.
41. Renatus M, et al. (1997) Structural mapping of the active site specificity determinants of human tissue-type plasminogen activator. Implications for the design of low molecular weight substrates and inhibitors. The Journal of biological chemistry 272(35):21713-21719.
42. Renatus M, et al. (1997) Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA. The EMBO journal 16(16):4797-4805.
43. Berman HM, et al. (2000) The Protein Data Bank. Nucleic Acids Research 28:235-242.
44. O’Boyle NM, et al. (2011) Open Babel: An open chemical toolbox. Cheminformatics 3(33).
45. Dallakyan S and Olson AJ (2015) Small-Molecule Library Screening by Docking with PyRx. Chemical Biology: Methods and Protocols, eds Hempel JE, Williams CH, and Hong CC (Springer New York, New York, NY), pp 243-250.
46. Kim S CJ, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, Zaslavsky L, Zhang J, Bolton EE. (2019) PubChem 2019 update: improved access to chemical data. Nucleic Acids Research.
47. BIOVIA DS (2018) BIOVIA Draw v18.1.
48. Schrodinger L (2018) The PyMOL Molecular Graphics System, Version 2.0
49. Wallace AC LR, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Engineering 8.
50. LB, Chi N, and Shi W (2015) Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes. Genet Mol Res 14(3):9518-9529.
51. Vassalli JD and Belin D (1987) Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett 214(1):187-191.
52. Jankun J and Skrzypczak-Jankun E (2001) Binding site of amiloride to urokinase plasminogen activator depends on species. Int J Mol Med 8(4):365-371.
53. Polinsky A, Goodman M, Williams KA, and Deber CM (1992) Minimum energy conformations of proline-containing helices. Biopolymers 32(4):399-406.
54. Sulimov VB, Kutov DC, and Sulimov AV (2018) Advances in Docking. Curr Med Chem.
55. Richardson JS, et al. (2018) Model validation: local diagnosis, correction and when to quit. Acta Crystallogr D Struct Biol 74(Pt 2):132-142.
56. Davatgaran-Taghipour Y, et al. (2017) Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective. Int J Nanomedicine 12:2689-2702.
57. Chen HY, et al. (2019) Chrysin inhibit human melanoma A375.S2 cell migration and invasion via affecting MAPK signaling and NF-kappaB signaling pathway in vitro. Environ Toxicol 34(4):434-442.
58. Rondeau E, et al. (1990) Nordihydroguaiaretic acid inhibits urokinase synthesis by phorbol myristate acetate-stimulated LLC-PK1 cells. Biochim Biophys Acta 1055(2):165-172.
59. Chiu YW, et al. (2011) Baicalein inhibits the migration and invasive properties of human hepatoma cells. Toxicol Appl Pharmacol 255(3):316-326.
2. Rabieian R, et al. (2018) Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis. J Cell Biochem 119(1):17-27.
3. Villalobos Acosta DMA, Chimal Vega B, Correa Basurto J, Fragoso Morales LG, and Rosales Hernandez MC (2018) Recent Advances by In Silico and In Vitro Studies of Amyloid-beta 1-42 Fibril Depicted a S-Shape Conformation. Int J Mol Sci 19(8).
4. Wilkinson DJ, Arques MDC, Huesa C, and Rowan AD (2019) Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics. Br J Pharmacol 176(1):38-51.
5. Wyganowska-Swiatkowska M, Tarnowski M, Murtagh D, Skrzypczak-Jankun E, and Jankun J (2019) Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review). Int J Mol Med 43(1):15-25.
6. Buckley BJ, Kelso MJ, Ali U, and Ranson M (2018) The Urokinase Plasminogen Activation System in Rheumatoid Arthritis: Pathophysiological Roles and Prospective Therapeutic Targets. Curr Drug Targets.
7. Jankun J, Khan OA, Mostafa HI, Sindhwani P, and Skrzypczak-Jankun E (2018) Can components of the plasminogen activation system predict the outcome of kidney transplants? Cent Eur J Immunol 43(2):222-230.
8. Jankun J and Skrzypczak-Jankun E (2009) Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn 119(6):410-417.
9. Madunic J (2018) The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role. Thromb Haemost 118(12):2020-2036.
10. Jeanneret V and Yepes M (2016) The Plasminogen Activation System Promotes Dendritic Spine Recovery and Improvement in Neurological Function After an Ischemic Stroke. Transl Stroke Res.
11. Liu YX (2004) Plasminogen activator/plasminogen activator inhibitors in ovarian physiology. Front Biosci 9:3356-3373.
12. Shahrour K, Keck R, and Jankun J (2015) Application of long-acting VLHL PAI-1 379 during sutureless partial nephrectomy in mice reduces bleeding. Biomed Res Int 2015:392862.
13. Li Y and Cozzi PJ (2007) Targeting uPA/uPAR in prostate cancer. Cancer Treat Rev 33(6):521-527.
14. McMahon BJ and Kwaan HC (2015) Components of the Plasminogen-Plasmin System as Biologic Markers for Cancer. Adv Exp Med Biol 867:145-156.
15. Rabbani SA and Xing RH (1998) Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. Int J Oncol 12(4):911-920.
16. Akudugu J, Serafin A, and Bohm L (2015) Further evaluation of uPA and PAI-1 as biomarkers for prostatic diseases. J Cancer Res Clin Oncol 141(4):627-631.
17. LeBeau AM, et al. (2015) Imaging active urokinase plasminogen activator in prostate cancer. Cancer Res 75(7):1225-1235.
18. Skovgaard D, Persson M, and Kjaer A (2017) Imaging of Prostate Cancer Using Urokinase-Type Plasminogen Activator Receptor PET. PET Clin 12(2):243-255.
19. Bode W and Renatus M (1997) Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function.Curr Opin Struct Biol 7(6):865-872.
20. Lamba D, et al. (1996) The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator. J Mol Biol 399 258(1):117-135.
21. Lin Z, et al. (2011) Structural basis for recognition of urokinase-type plasminogen activator by plasminogen activator inhibitor-1. J Biol Chem 286(9):7027-7032.
22. Spraggon G, et al. (1995) The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure 3(7):681-691.
23. Takehara S, et al. (2009) The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability. J Mol Biol 388(1):11-20.
24. Bhongade BA, Gouripur VV, and Gadad AK (2005) 3D-QSAR CoMFA studies on trypsin-like serine protease inhibitors: a comparative selectivity analysis. Bioorg Med Chem 13(8):2773-2782.
25. Gladysz R, et al. (2015) Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold. J Med Chem 58(23):9238-9257.
26. Renatus M, Bode W, Huber R, Sturzebecher J, and Stubbs MT (1998) Structural and functional analyses of benzamidine-based inhibitors in complex with trypsin: implications for the inhibition of factor Xa, tPA, and urokinase. J Med Chem 41(27):5445-5456.
27. Zhang D, et al. (2017) Role of Vascular Endothelial Cells in Disseminated Intravascular Coagulation Induced by Seawater Immersion in a Rat Trauma Model. Biomed Res Int 2017:5147532.
28. Bello M (2018) Advances in Theoretical Studies on the Design of Single Boron Atom Compounds. Curr Pharm Des 24(29):3466-3475.
29. Gns HS, Gr S, Murahari M, and Krishnamurthy M (2019) An update on Drug Repurposing: Re-written saga of the drug’s fate. Biomed Pharmacother 110:700-716.
30. Hoi PM, et al. (2015) Recent advances in structure-based drug design and virtual screening of VEGFR tyrosine kinase inhibitors. Methods 71:85-91.
31. Tamay-Cach F, et al. (2016) In Silico Studies Most Employed in the Discovery of New Antimicrobial Agents. Curr Med Chem 23(29):3360-3373.
32. Wang SH and Yu J (2018) Structure-based design for binding peptides in anticancer therapy. Biomaterials 156:1-15.
33. Daniyan MO and Ojo OT (2019) In silico identification and evaluation of potential interaction of Azadirachta indica phytochemicals with Plasmodium falciparum heat shock protein 90. J Mol Graph Model 87:144-164.
34. Foroughi K, Khaksari M, and Shayannia A (2018) Molecular Docking Studies of Methamphetamine and Amphetamine-Related Derivatives as an Inhibitor against dopamine Receptor. Curr Comput Aided Drug Des.
35. Kumar S, Khatik GL, and Mittal A (2018) In-silico Molecular Docking Study to Search New SGLT2 Inhibitor based on Dioxabicyclo[3.2.1] octane Scaffold. Curr Comput Aided Drug Des.
36. Sadati SM, Gheibi N, Ranjbar S, and Hashemzadeh MS (2019) Docking study of flavonoid derivatives as potent inhibitors of influenza H1N1 virus neuraminidase. Biomed Rep 10(1):33-38.
37. Sepehri B, Rezaei M, and Ghavami R (2018) The in silico identification of potent anti-cancer agents by targeting the ATP binding site of the N-domain of HSP90. SAR QSAR Environ Res 29(7):551-565.
38. Trott O and Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455-461.
39. Kang YN, Stuckey, J.A., Nienaber, V., Giranda, V. (2012) Crystal Structure of the Urokinase. To be published.
40. Zeslawska E, et al. (2000) Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design. Journal of molecular biology 301(2):465-475.
41. Renatus M, et al. (1997) Structural mapping of the active site specificity determinants of human tissue-type plasminogen activator. Implications for the design of low molecular weight substrates and inhibitors. The Journal of biological chemistry 272(35):21713-21719.
42. Renatus M, et al. (1997) Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA. The EMBO journal 16(16):4797-4805.
43. Berman HM, et al. (2000) The Protein Data Bank. Nucleic Acids Research 28:235-242.
44. O’Boyle NM, et al. (2011) Open Babel: An open chemical toolbox. Cheminformatics 3(33).
45. Dallakyan S and Olson AJ (2015) Small-Molecule Library Screening by Docking with PyRx. Chemical Biology: Methods and Protocols, eds Hempel JE, Williams CH, and Hong CC (Springer New York, New York, NY), pp 243-250.
46. Kim S CJ, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, Zaslavsky L, Zhang J, Bolton EE. (2019) PubChem 2019 update: improved access to chemical data. Nucleic Acids Research.
47. BIOVIA DS (2018) BIOVIA Draw v18.1.
48. Schrodinger L (2018) The PyMOL Molecular Graphics System, Version 2.0
49. Wallace AC LR, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Engineering 8.
50. LB, Chi N, and Shi W (2015) Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes. Genet Mol Res 14(3):9518-9529.
51. Vassalli JD and Belin D (1987) Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett 214(1):187-191.
52. Jankun J and Skrzypczak-Jankun E (2001) Binding site of amiloride to urokinase plasminogen activator depends on species. Int J Mol Med 8(4):365-371.
53. Polinsky A, Goodman M, Williams KA, and Deber CM (1992) Minimum energy conformations of proline-containing helices. Biopolymers 32(4):399-406.
54. Sulimov VB, Kutov DC, and Sulimov AV (2018) Advances in Docking. Curr Med Chem.
55. Richardson JS, et al. (2018) Model validation: local diagnosis, correction and when to quit. Acta Crystallogr D Struct Biol 74(Pt 2):132-142.
56. Davatgaran-Taghipour Y, et al. (2017) Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective. Int J Nanomedicine 12:2689-2702.
57. Chen HY, et al. (2019) Chrysin inhibit human melanoma A375.S2 cell migration and invasion via affecting MAPK signaling and NF-kappaB signaling pathway in vitro. Environ Toxicol 34(4):434-442.
58. Rondeau E, et al. (1990) Nordihydroguaiaretic acid inhibits urokinase synthesis by phorbol myristate acetate-stimulated LLC-PK1 cells. Biochim Biophys Acta 1055(2):165-172.
59. Chiu YW, et al. (2011) Baicalein inhibits the migration and invasive properties of human hepatoma cells. Toxicol Appl Pharmacol 255(3):316-326.
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2020-05-06
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Talbot, B., & Jankun, J. (2020). Specific inhibitors of urokinase plasminogen activator for treatment of cancers; In silico approach. Translation: The University of Toledo Journal of Medical Sciences, 7, 15–20. https://doi.org/10.46570/utjms.vol7-2020-346
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