Selection of Efficient Inhibitors for Caspas-9 according to Structure-Based Pharmacophore Screening Strategy and Molecular Dynamics Simulations
Trends in Peptide and Protein Sciences,
Vol. 2 No. 1 (2017),
1 January 2018
,
Page 35-43
https://doi.org/10.22037/tpps.v2i1.19189
Abstract
Caspases are enzymes which are the main pathways for apoptosis. Any irregulation in their functions causes increase or decrease in cell death, which result in autoimmune disease or cancer, respectively. In this study, structure-based pharmacophore drug discovery method as a virtual screening was used to discover selective inhibitors for caspase-9. This enzyme is an initiator caspase that is the main pathway in Alzheimer’s disease. A pharmacophore model was developed by investigating essential interactions among the reported potent inhibitors employing a docking analysis methodology. Applying pharmacophore virtual screening, nine compounds from both National Cancer Institute (NCI), and ZINC databases were filtered as potent inhibitors of caspase-9. The efficiency of the discovered compounds was further investigated by docking studies.
HIGHLIGHTS
•Caspase-9 is an important enzyme for apoptosis and its activity is pivotal in cell death.
•A computational design of small molecular inhibitors for caspase-9 performed by structure-based pharmacophore model.
•9 compounds from both National Cancer Institute (NCI) and ZINC databases were discovered as potent inhibitors.
- Alzheimer’s disease
- Virtual screening
- Pharmacophore
- Docking
- Caspase-9
- Inhibitor
How to Cite
References
Braun, J. S., Novak, R., Herzog, K. H., Bodner, S. M., Cleveland, J. L. and E. I. Tuomanen, (1999). "Neuroprotection by a caspase inhibitor in acute bacterial meningitis." Nature Medicine, 5(3): 298-302.
Chao, Y., Shiozaki, E. N., Srinivasula, S. M., Rigotti, D. J., Fairman R. and Y. Shi, (2005). "Engineering a dimeric caspase-9: a re-evaluation of the induced proximity model for caspase activation." PLoS Biology, 3(6): e183.
Chong, Z. Z., Li, F. and K. Maiese, (2005). "Employing new cellular therapeutic targets for Alzheimer's disease: a change for the better?" Current Neurovascular Research, 2(1): 55-72.
Cohen, G. M. (1997). "Caspases: the executioners of apoptosis." Biochemical Journal, 326 (Pt 1): 1-16.
Cullen, S. P. and S. J. Martin, (2009). "Caspase activation pathways: some recent progress." Cell Death & Differentiation, 16(7): 935-938.
Cursio, R., Gugenheim, J., Ricci, J. E., Crenesse, D., Rostagno, P., Maulon, L., Saint-Paul, M. C., Ferrua, B. and A. P. Auberger, (1999). "A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis." The FASEB Journal, 13(2): 253-261.
Denault, J. B. and G. S. Salvesen, (2002). "Caspases: keys in the ignition of cell death." Chemical Reviews, 102(12): 4489-4500.
Grutter, M. G. (2000). "Caspases: key players in programmed cell death." Current Opinion in Structural Biology, 10(6): 649-655.
Lee, D., Long, S. A., Adams, J. L., Chan, G., Vaidya, K. S., Francis, T. A., Kikly, K., Winkler, J. D., Sung, C. M., Debouck, C., Richardson, S., Levy, M. A., DeWolf, W. Keller, E., P. M., Tomaszek, T., Head, M. S., Ryan, M. D., Haltiwanger, R. C., Liang, P. H., Janson, C. A., McDevitt, P. J., Johanson, K., Concha, N. O., Chan, W., Abdel-Meguid, S. S., Badger, A. M., Lark, M. W., Nadeau, D. P., Suva, L. J., Gowen, M. and M. E. Nuttall, (2000). "Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality." Journal of Biological Chemistry, 275(21): 16007-16014.
Liu, T., Lin, Y., Wen, X., Jorissen, R. N. and M. K. Gilson, (2007). "BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities." Nucleic Acids Research, 35(Database issue): D198-201.
Mocanu, M. M., Baxter, G. F. and D. M. Yellon (2000). "Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury." British Journal of Pharmacology, 130(2): 197-200.
Philchenkov, A. (2004). "Caspases: potential targets for regulating cell death." Journal of Cellular and Molecular Medicine, 8(4): 432-444.
Pronk, S., Pall, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., Shirts, M. R., Smith, J. C., Kasson, P. M., van der Spoel, D., Hess, B. and E. Lindahl, (2013). "GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit." Bioinformatics, 29(7): 845-854.
Renatus, M., Stennicke, H. R., Scott, F. L., Liddington, R. C. and G. S. Salvesen, (2001). "Dimer formation drives the activation of the cell death protease caspase 9." Proceedings of the National Academy of Sciences USA, 98(25): 14250-14255.
Rohn, T. T. (2010). "The role of caspases in Alzheimer's disease; potential novel therapeutic opportunities." Apoptosis, 15(11): 1403-1409.
Rohn, T. T. and E. Head, (2009). "Caspases as therapeutic targets in Alzheimer's disease: is it time to "cut" to the chase?" International Journal of Clinical and Experimental Pathology, 2(2): 108-118.
Rohn, T. T., Rissman, R. A., Davis, M. C., Kim, Y. E., Cotman, C. W. and E. Head (2002). "Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain." Neurobiology of Disease, 11(2): 341-354.
Rudel, T. (1999). "Caspase inhibitors in prevention of apoptosis." Herz, 24(3): 236-241.
Sali, A. and T. L. Blundell, (1993). "Comparative protein modelling by satisfaction of spatial restraints." Journal of Molecular Biology, 234(3): 779-815.
Schulz, J. B., Weller, M. and M. A. Moskowitz, (1999). "Caspases as treatment targets in stroke and neurodegenerative diseases." Annals of Neurology, 45(4): 421-429.
Schuttelkopf, A. W. and D. M. van Aalten, (2004). "PRODRG: a tool for high-throughput crystallography of protein-ligand complexes." Acta Crystallographica Section D: Structural Biology, 60(Pt 8): 1355-1363.
Shi, Y. (2002). "Mechanisms of caspase activation and inhibition during apoptosis." Molecular Cell, 9(3): 459-470.
Shi, Y. (2005). "Activation of Initiator Caspases: History, Hypotheses, and Perspectives." Journal of Cancer Molecules, 1(1): 9-18.
Shiozaki, E. N., Chai, J., Rigotti, D. J., Riedl, S. J., Li, P., Srinivasula, S. M., Alnemri, E. S., Fairman, R. and Y. Shi, (2003). "Mechanism of XIAP-mediated inhibition of caspase-9." Molecular Cell, 11(2): 519-527.
Talanian, R. V., Brady, K. D. and V. L. Cryns, (2000). "Caspases as targets for anti-inflammatory and anti-apoptotic drug discovery." Journal of Medicinal Chemistry, 43(18): 3351-3371.
Wang, R., Lu, Y. and S. Wang, (2003). "Comparative evaluation of 11 scoring functions for molecular docking." Journal of Medicinal Chemistry, 46(12): 2287-2303.
Wolber, G. and T. Langer, (2005). "LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters." Journal of Chemical Information and Modeling, 45(1): 160-169.
Yang, W., Guastella, J., Huang, J. C., Wang, Y., Zhang, L., Xue, D., Tran, M., Woodward, R., Kasibhatla, S., Tseng, B., Drewe, J. and S. X. Cai, (2003). "MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity." British Journal of Pharmacology, 140(2): 402-412.
Yaoita, H., Ogawa, K., Maehara, K. and Y. Maruyama (1998). "Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor." Circulation, 97(3): 276-281.
Yoshimori, A., Sakai, J., Sunaga, S., Kobayashi, T., Takahashi, S., Okita, N., Takasawa, R. and S. Tanuma, (2007). "Structural and functional definition of the specificity of a novel caspase-3 inhibitor, Ac-DNLD-CHO." BMC Pharmacology, 7: 8.
- Abstract Viewed: 251 times
- PDF Downloaded: 148 times