2-Phenylethyne-1-Sulfonamide Derivatives as New Drugs Candidates for Heat Shock Protein 70 and Doublecortin-like Kinase

Abstract

Under physiological conditions HSP70 plays crucial roles in protein homeostasis. This protein is overexpressed in many types of cancer cells and increased levels of HSP70 is closely associated with tumorigenesis and poor clinical outcomes. The present study was designed to evaluate in silico assessment of newly designed 30 different 2-Phenylethyne-1-Sulfonamide derivatives potential heat shock protein 70 inhibitors. The mentioned structures were optimized at B3LYP/6-31+G(d,p) level in water and active sites of them are determined. Then, molecular docking calculations were done between the related structures and 4PO2 and 5JZN. It is found that compound (5), (12) and (20) were found as the better ones than those of compound (1) and (2). Drug likeness studies were performed via pharmacological ADME (absorption, distribution, metabolism, and excretion) properties estimation and the drug properties of (5) and (12) were found as the better than those of compound (1), (2) and (20).

Keywords

• HSP70 Inhibitors
• Drug Design
• Molecular Dynamics
• Molecular Docking
• ADME Analyses

Project Number

RGD-020

References

1. S. Chatterjee, T. F. Burns, Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach, Int J Mol Sci. 18 (2017) E1978.
2. P. C. Ikwegbue, P. Masamba, B. E. Oyinloye, A. P. Kappo, Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer, Pharmaceuticals (Basel) 11 (2018) E2.
3. M. V. Powers, P. A. Clarke, P. Workman, Death by chaperone: HSP90, HSP70 or both?, Cell Cycle. 8 (2009) 518-526.
4. M. Y. Sherman, V. L. Gabai, Hsp70 in cancer: back to the future, Oncogene. 34 (2015) 4153-4161.
5. R. Schlecht, S R. Scholz, H. Dahmen, A. Wegener, C. Sirrenberg, D. Musil, J. Bomke, H. M. Eggenweiler, M. P. Mayer, B. Bukau, Functional Analysis of Hsp70 Inhibitors, PLoS One 8 (2013) e78443.
6. J. Radons, The human HSP70 family of chaperones: where do we stand?, Cell Stress Chaperones. 21 (2016) 379-404.
7. A. Rodina, P. D. Patel, Y. Kang, Y. Patel, I. Baaklini, M. J. Wong, T. Taldone, P. Yan, C. Yang, R. Maharaj, A. Gozman, M. R. Patel, H. J. Patel, W. Chirico, H. Erdjument-Bromage, T. T. Talele, J. C. Young, G. Chiosis, Identification of an Allosteric Pocket on Human Hsp70 Reveals a Mode of Inhibition of This Therapeutically Important Protein, Chem Biol. 20 (2013) 1469-1480.
8. D. Lanneau, A. de Thonel, S, Maurel, C. Didelot, C. Garrido, Apoptosis Versus Cell Differentiation, Prion. 1 (2007) 53-60.

9. M. E. Murphy, The HSP70 family and cancer, Carcinogenesis. 34 (2013) 1181-1188.
10. A. R. Goloudina, O. N. Demidov, C. Garrido, Inhibition of HSP70: A challenging anti-cancer strategy, Cancer Lett. 325 (2012) 117-124.
11. G. D.Lianos, G. A. Alexiou, A. Mangano, A. Mangano, S. Rausei, L. Boni, G. Dionigi, D. H. Roukos, The role of heat shock proteins in cancer, Cancer Lett. 360 (2015) 114-118.
12. S. Kumar, J. Stokes, U. P Singh, K. Scissum Gunn, A. Acharya, U. Manne, M. Mishra, Targeting Hsp70: A possible therapy for cancer, Cancer Lett. 374 (2016) 156-166.
13. J. A.Yaglom, V. L. Gabai, M. Y. Sherman, High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways, Cancer Res. 67 (2007) 2373-2381.
14. E. Zorzi, P. Bonvini, Inducible Hsp70 in the Regulation of Cancer Cell Survival: Analysis of Chaperone Induction, Expression and Activity, Cancers (Basel) 3 (2011) 3921-3956.
15. G. Jego, A. Hazoumé, R. Seigneuric, C. Garrido, Targeting heat shock proteins in cancer, Cancer Lett. 332 (2013) 275-285.
16. M. V. Powers, K. Jones, C. Barillari, I. Westwood, R. L. van Montfort, P. Workman, Targeting HSP70: The second potentially druggable heat shock protein and molecular chaperone?, Cell Cycle. 9 (2010) 1542-1550.
17. H. Wang, L. Bu, C. Wang, Y. Zhang, H. Zhou, X. Zhang, W. Guo, C. Long, D. Guo, X. Sun, The Hsp70 inhibitor 2-phenylethynesulfonamide inhibits replication and carcinogenicity of Epstein-Barr virus by inhibiting the molecular chaperone function of Hsp70, Cell Death Dis. 9 (2018) 734.
18. G. M. Balaburski, J. I. Leu, N. Beeharry, S. Hayik, M. D. Andrake, G. Zhang, M. Herlyn, J. Villanueva, R. L. Jr. Dunbrack, T. Yen, D. L. George, M. E. Murphy, A modified HSP70 inhibitor shows broad activity as an anticancer agent, Mol Cancer Res. 11 (2013) 219-229.
19. R. D. Dennington II, T. A. Keith and J. M. Millam, GaussView 5.0, Wallingford, CT, 2009.
20. Perkin Elmer, ChemBioDraw Ultra Version (15.1.0.144), CambridgeSoft Waltham, MA, USA, 2016.
21. Gaussian 09, Gaussian AS64L-G09RevD.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
22. A. D. Becke, Density‐functional thermochemistry. III. The role of exact exchange, J. Chem. Phys. 98 (1993) 5648-5652.
23. R. Ditchfield, W. J. Hehre, J. A. Pople, Self‐Consistent Molecular‐Orbital Methods. IX. An Extended Gaussian‐Type Basis for Molecular‐Orbital Studies of Organic Molecules, J. Chem. Phys. 54 (1971) 724-728.
24. W. J. Hehre, R. Ditchfield, J. A. Pople, Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules, J. Chem. Phys. 56 (1972) 2257-2261.
25. P. C. Hariharan, J. A. Pople, The influence of polarization functions on molecular orbital hydrogenation energies, Theor. Chem. Acc. 28 (1973) 213-222.
26. P. C. Hariharan, J. A. Pople, Accuracy of AH n equilibrium geometries by single determinant molecular orbital theory, Mol. Phys. 27 (1974) 209-214.
27. M. S. Gordon, The isomers of silacyclopropane, Chem. Phys. Lett. 76 (1980) 163-168.
28. M. M. Francl, W. J. Pietro, W. J. Hehre, J. S. Binkley, D. J. DeFrees, J. A. Pople, M. S. Gordon, Self‐consistent molecular orbital methods. XXIII. A polarization‐type basis set for second‐row elements, J. Chem. Phys. 77 (1982) 3654-3665.
29. R. C. Binning Jr., L. A. Curtiss, Compact contracted basis sets for third‐row atoms: Ga–Kr, J. Comp. Chem. 11 (1990) 1206-1216.
30. J. –P. Blaudeau, M. P. McGrath, L. A. Curtiss, L. Radom, Extension of Gaussian-2 (G2) theory to molecules containing third-row atoms K and Ca, J. Chem. Phys. 107 (1997) 5016-5021.
31. V. A. Rassolov, J. A. Pople, M. A. Ratner, T. L. Windus, 6-31G* basis set for atoms K through Zn, J. Chem. Phys. 109 (1998) 1223-1229.
32. V. A. Rassolov, M. A. Ratner, J. A. Pople, P. C. Redfern, L. A. Curtiss, 6‐31G* basis set for third‐row atoms, J. Comp. Chem. 22 (2001) 976-984.
33. Gaussian 09, Gaussian Gaussian IA32W-G09RevA.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
34. N. M. O'Boyle, A. L. Tenderhold, K. M. Langner, A library for package‐independent computational chemistry algorithms, J. Comp. Chem. 29 (2008) 839-845.
35. E. Harder, W. Damm, J. Maple, C. Wu, M. Reboul, J. Y. Xiang, L. Wang, D. Lupyan, M. K. Dahlgren, J. L. Knight, J. W. Kaus, D. Cerutti, G. Krilov, W. L. Jorgensen, R. Abel, R. A. Friesner, OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins, J. Chem. Theory Comput. 12 (2016) 281-296.
36. R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, P. C. Sanschagrin, D. T. Mainz, Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J. Med. Chem. 49 (2006) 6177-6196.
37. T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye, W. T. Pollard, J. L. Banks, Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening, J. Med. Chem. 47 (2004) 1750-1759.
38. R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, M. P. Repasky, E. H. Knoll, D. E. Shaw, M. Shelley, J. K. Perry, P. Francis, P. S. Shenkin, Glide:  A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy, J. Med. Chem. 47 (2004) 1739-1749.
39. A. Daina, O. Michielin, V. Zoete, iLOGP: A Simple, Robust, and Efficient Description of n-Octanol/Water Partition Coefficient for Drug Design Using the GB/SA Approach, J. Chem. Inf. Model. 54(12) (2014) 3284-3301.
40. P. Zhang, J. I. -Ju Leu, M. E. Murphy, D. L. George, R. Marmorstein, Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with Peptide substrate, PLOS One 9(7) (2014) e103518.
41. O. Patel, W. Dai, M. Mentzel, M. D. W. Griffin, J. Serinoux, Y. Gay, S. Fischer, S. Sterle, A. Kropp, C. J. Burns, M. Ernst, M. Buchert, I. S. Lucet, Biochemical and Structural Insights into Doublecortin-like Kinase Domain 1, Structure 24 (2016) 1550-1561.