DOI QR코드

DOI QR Code

Hologram Based QSAR Analysis of Caspase-3 Inhibitors

  • Sathya., B (Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology)
  • Received : 2018.04.17
  • Accepted : 2018.06.25
  • Published : 2018.06.30

Abstract

Caspases, a family of cysteinyl aspartate-specific proteases plays a central role in the regulation and the execution of apoptotic cell death. Caspase-3 has been proven to be an effective target for reducing the amount of cellular and tissue damage because the activation of caspases-3 stimulates a signalling pathway that ultimately leads to the death of the cell. In this study, Hologram based Quantitative Structure Activity Relationship (HQSAR) models was generated on a series of Caspase-3 inhibitors named 3, 4-dihydropyrimidoindolones derivatives. The best HQSAR model was obtained using atoms, bonds, and hydrogen atoms (A/B/H) as fragment distinction parameter using hologram length 61 and 3 components with fragment size of minimum 5 and maximum 8. Significant cross-validated correlation coefficient ($q^2=0.684$) and non cross-validated correlation coefficients ($r^2=0.754$) were obtained. The model was then used to evaluate the eight external test compounds and its $r^2_{pred}$ was found to be 0.559. Contribution map show that presence of pyrrolidine sulfonamide ring and its bulkier substituent's makes big contributions for improving the biological activities of the compounds.

Keywords

References

  1. M. D. Jacobson, M. Weil, and M. C Raff, "Pro-grammed cell death in animal development", Cell, Vol. 88, pp. 347-354, 1997. https://doi.org/10.1016/S0092-8674(00)81873-5
  2. G. M. Cohen, "Caspases: the executioners of apoptosis", Biochem. J., Vol. 326, pp. 1-16, 1997. https://doi.org/10.1042/bj3260001
  3. C. B. Thonberry and Y. Lazebnik, "Caspases: enemied within", Science, Vol. 281, pp. 1312-1316, 1998. https://doi.org/10.1126/science.281.5381.1312
  4. D. W. Nicolson, "Caspase structure, proteolytic substrates, and function during apoptotic cell death", Cell Death Differ., Vol. 6, pp. 1028-1042, 1999. https://doi.org/10.1038/sj.cdd.4400598
  5. J. Wang, M. J. Lenardo, "Roles of caspases in apoptosis, development and cytokine maturation revealed by homozygous gene deficiencies", J. Cell Sci., Vol. 113, pp. 753-757, 2000.
  6. M. Endres, S. Namura, M. Shomizu-Sasamata. C. Waeber, L. Zhang, T. Gomez-Isla, B. T. Hyman, and M. A. Moskowitz, "Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of caspase family", J. Cereb. Blood Flow Metab., Vol. 18, pp. 238-247, 1998. https://doi.org/10.1097/00004647-199803000-00002
  7. K. M. Boatright and G. S. Salvesen, "Mechanisms of caspase activation", Curr. Opin. Cell Biol., Vol. 15, pp. 725-731, 2003. https://doi.org/10.1016/j.ceb.2003.10.009
  8. B. A. Callus and D. L. Vaux, "Caspase inhibitors: viral, cellular and chemical", Cell Death Differ., Vol. 14, pp. 73-78, 2007. https://doi.org/10.1038/sj.cdd.4402034
  9. B. H. Han, D. Xu, J. Cho, Y. Han, S. Xanthoudakis, S. Roy, J. Tam, J. Vaillancourt, J. Colucci, R. Siman, A. Giroux, G. S. Robertson, R. Zamboni, D. W. Nicholson, and D. M. Holtzman, "Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury", J. Biol. Chem., Vol. 277, pp. 30128-30136, 2002. https://doi.org/10.1074/jbc.M202931200
  10. R. S. Hotchkiss, K. C. Chang , P. E. Swanson, K. W. Tinsley, J. J. Hui, P. Klender, S. Xanthoudakis, S. Roy, C. Black, E. Grimm, R. Aspiotis, Y. Han, D. W. Nicholson, and I. E. Karl, "Caspase inhibitors improves survival in sepsis: a critical role of the lymphocyte", Nat. Immunol., Vol. 1, pp. 496-501, 2000. https://doi.org/10.1038/82741
  11. D. Lee, S. A. Long, J. H. Murray, J. L. Adams, M. E. Nuttall, D. P. Nadeau, K. Kikly, J. D. Winkler, C.-M. Sung, M. D. Ryan, M. A. Levy, P. M. Keller, and W. E. DeWolf, "Potent and selective non pep- tide inhibitors of caspase 3 and 7", J. Med. Chem., Vol. 44, pp. 2015-2026, 2001. https://doi.org/10.1021/jm0100537
  12. H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama, "Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor", Circulation, Vol. 97, pp. 276-281, 1998. https://doi.org/10.1161/01.CIR.97.3.276
  13. J. Schoenberger, J. Bauer, J. Moosbauer, C. Eilles, and D. Grimm, "Innovative strategies in in-vivo apoptosis imaging", Curr. Med. Chem., Vol. 15, pp. 187-194, 2008. https://doi.org/10.2174/092986708783330647
  14. D. K. Perry, M. J. Smyth, H. R. Stennicke, G. S. Salvessan, P. Duriez, G. G. Poirier, and Y. A. Han- nun, "Zinc is a potent inhibitor of the apoptotic protease, caspase-3. a novel target for zinc in the inhibition of apoptosis", J. Biol. Chem., Vol. 272, pp. 18530-18533, 1997. https://doi.org/10.1074/jbc.272.30.18530
  15. A. G. Porter and R. U. Janicke, "Emerging roles of caspase 3 in apoptosis", Cell Death Differ., Vol. 6, pp. 99-104, 1999. https://doi.org/10.1038/sj.cdd.4400476
  16. C. W. Scott, C. Sobotka-Brinker, D. E. Wilkins, R. T. Jacobs, J. J. Folmer, W. J. Frazee, R. V. Bhat, S. V. Ghanekar, and D. Aharony, "Novel small molecule inhibitors of caspase-3 block cellular and bio-chemical features of apoptosis", J. Pharmacol. Exp. Ther., Vol. 304, pp. 433-440, 2003. https://doi.org/10.1124/jpet.102.039651
  17. D. V. Kravchenko, V. M. Kysil, S. E. Tkachenko, S. Maliarchouk, I. M. Okun, and A. V. Ivanchtch- enko, "Pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors. Synthesis and SAR of 2-sub- stituted 4-methyl-8-(morpholine-4-sulfonyl)-pyrrolo [3,4-c]quinoline-1,3-diones", Eur. J. Med. Chem., Vol. 40, pp. 1377-1383, 2005. https://doi.org/10.1016/j.ejmech.2005.07.011
  18. W. Chu, J. Zhang, C. Zeng, J. Rothfuss, Z. Tu, Y. Chu, D. E. Reichert, M. J. Welch, and R. H. Mach, "N-Benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: Synthesis, in vitro activity and molecular modeling studies", J. Med. Chem., Vol. 48, pp. 7637-7647, 2005. https://doi.org/10.1021/jm0506625
  19. L. M. Havran, D. C. Chong, W. E. Childers, P. J. Dollings, A. Dietrich, B. L. Harrison, V. Marathias, G. Tawa, A. Aulabaugh, R. Cowling, B. Kapoor, W. Xu, L. Mosyak, F. Moy, W.-T. Hum, A. Wood, and A. J. Robichaud, "3.4-Dihydropyrimido (1,2-a indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3", Bioorg. Med. Chem., Vol. 17, pp. 7755-7768, 2009. https://doi.org/10.1016/j.bmc.2009.09.036
  20. B. Sathay, "Docking study of corticotropin-releas-ing factor-1 receptor with its antagonists", J. Chosun Natural Sci., Vol. 11, pp. 19-24, 2018.
  21. Tripos Sybyl, HQSAR manual.
  22. C. L. Waller, "A comparative QSAR study using CoMFA, HQSAR, and FRED/SKEYS paradigms for estrogen receptor binding affinities of structur- ally diverse compounds", J. Chem. Inf. Comput. Sci., Vol. 44, pp. 758-765, 2004. https://doi.org/10.1021/ci0342526
  23. W. Tong, D. R. Lowis, R. Perkins, Y. Chen, W. J. Welsh, D. W. Goddette, T. W. Heritage, and D. M. Sheehan, "Evaluation of quantitative structure-activity relationship methods for large-scale prediction of chemicals binding to the estrogen receptor", J. Chem. Inf. Comput. Sci., Vol. 38, pp. 669-677, 1998. https://doi.org/10.1021/ci980008g
  24. M. Thirumurthy, K. Gugan, C. G. Gadhe, and J. C. Segung, "QSAR analysis on PfPK7 inhibitors using HQSAR, CoMFA and CoMSIA", Med. Chem. Res., Vol. 21, pp. 681-693, 2012. https://doi.org/10.1007/s00044-011-9572-x
  25. T. W Heritage and D. R. Lowis, "Molecular Holo-gram QSAR", In Rational Drug Design, Washing-ton: American Chemical Society, ACS Symposium Series, Vol. 719, pp 212-225, 2000.
  26. D. A Winkler and F. R. Burden, "Holographic QSAR of benzodiazepines", Quantitative Structure-Activity Relationships, Vol. 17, pp. 224-231, 1998. https://doi.org/10.1002/(SICI)1521-3838(199806)17:03<224::AID-QSAR224>3.3.CO;2-Y
  27. S. Wold, "Cross-validatory estimation of the num- ber of components in factor and principal component model", Technometrics, Vol. 20, pp. 397-405, 1978. https://doi.org/10.1080/00401706.1978.10489693
  28. B. Sathya, "Hologram based QSAR analysis of xan-thine oxidase inhibitors", J. Chosun Natural Sci., Vol. 10, pp. 202-208, 2017.
  29. B. Sathya, "Homology modelling of chemerin like receptor-1 (CMKLR1): potential target for treating type II diabetes", J. Chosun Natural Sci., Vol. 10, pp. 20-26, 2017. https://doi.org/10.13160/ricns.2017.10.1.20