Journal of Integrative Natural Science (통합자연과학논문집)

The Basic Science Institute Chosun University (조선대학교 기초과학연구원)
권호 표지
DOI QR코드

DOI QR Code

Comparative Molecular Similarity Indices Analysis of CXCR-2 Inhibitors

  • B, Sathya. (Department of Genetic Engineering, School of Bioengineering, SRM University)
  • Received : 2016.07.21
  • Accepted : 2016.09.25
  • Published : 2016.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils and it regulates the neutrophilic inflammation in the lung diseases. CXCR2 antagonist may reduce the neutrophil chemotaxis and alter the inflammatory response. Hence, in the present study, ligand based Comparative Molecular Similar Indices Analysis (CoMSIA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The optimum CoMSIA model was obtained with statistically significant cross-validated coefficients ($q^2$) of 0.582 and conventional coefficients ($r^2$) of 0.987 with steric, electrostatic, hydrophobic, donor and acceptor fields. The contour maps suggest the important structural modifications and this study can be used to guide the development of potent CXCR2 antagonist.

Keywords

References

  1. M. Uguccioni, M. D'Apuzzo, M. Loetscher, B. Dewald, and M. Baggiolini, "Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes", Eur. J. Immunol., Vol. 25, pp. 64-68, 1995. https://doi.org/10.1002/eji.1830250113
  2. R. W. Chapman, J. E. Phillips, R. W. Hipkin, A. K. Curran, D. Lundell, and J. S. Fine, "CXCR2 antagonists for the treatment of pulmonary disease", Pharmacol. Therapeut., Vol. 212, pp. 55-68, 2009.
  3. J. Reutershan, A. Basit, E. V. Galkina, and K. Ley, "Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced lung injury", Am. J. Physiol-Lung C., Vol. 289, pp. L807-L815, 2005. https://doi.org/10.1152/ajplung.00477.2004
  4. S. L. Traves, S. J. Smith, P. J. Barnes, and L. E. Donnelly, "Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2", J. Leukocyte. Biol., Vol. 76, pp. 441-450, 2004. https://doi.org/10.1189/jlb.1003495
  5. K. J.Eash, A. M. Greenbaum, P. K. Gopalan, and D. C. Link, "CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow", J. Clin. Invest., Vol. 120, pp. 2423-2431, 2010. https://doi.org/10.1172/JCI41649
  6. R. A. Pauwels and K. F. Rabe, "Burden and clinical features of chronic obstructive pulmonary disease (COPD)", Lancet, Vol. 364, pp. 613-620, 2004. https://doi.org/10.1016/S0140-6736(04)16855-4
  7. E. H. Bel, A. Sousa, L. Fleming, A. Bush, K. F Chung, J. Versnel, A. H. Wagener, S. S. Wagers, P. J. Sterk, and C. H. Compton, "Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI)", Thorax, 2010.
  8. P. Anderson, "Emerging therapies in cystic fibrosis", Ther. Adv. Respir. Dis., Vol. 4, pp. 177-185, 2010. https://doi.org/10.1177/1753465810371107
  9. P. M. Murphy, "Neutrophil receptors for interleukin-8 and related CXC chemokines", Semin. Hematol., Vol. 34, pp. 311-318, 1997.
  10. W. Sippl, "3D-QSAR - Applications, recent advances, and limitations", in Recent Advances in QSAR Studies: Methods and Applications, Heidelberg: Springer, 2010
  11. B. Sathya and M. Thirumurthy, "Pharmacophore based comparative molecular field analysis of CRTh2 antagonists", J. Chosun Natural Sci., Vol. 8, pp. 89-98, 2015. https://doi.org/10.13160/ricns.2015.8.2.89
  12. B. Sathya and M. Thirumurthy, "Comparative molecular field analysis of caspase-3 inhibitors", J. Chosun Natural Sci., Vol. 7, pp. 166-172, 2014. https://doi.org/10.13160/ricns.2014.7.3.166
  13. M. Thirumurthy, "Modeling aided lead design of FAK inhibitors", J. Chosun Natural Sci., Vol. 4, pp. 266-272, 2011.
  14. M. Thirumurthy, "3D-QSAR studies of 3,5-disubstituted quinolines inhibitors of c-Jun N-terminal kinase-3", J. Chosun Natural Sci., Vol. 4, pp. 216-221, 2011.
  15. D. W. Porter , M. Bradley, Z. Brown, S. J. Charlton, B. Cox, P. Hunt, D. Janus, S. Lewis, P. Oakley, D. O'Connor, J. Reilly, N. Smith, and N. J. Press, "The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists", Bioorg. Med. Chem. Lett., Vol. 24, pp. 3285-3290, 2014. https://doi.org/10.1016/j.bmcl.2014.06.011
  16. SYBYL Software, Version X 2.0., 2006, Tripos Associates Inc, St. Louis, USA.
  17. G. Klebe, U. Abraham, and T. Mietzner, "Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity", J. Med. Chem., Vol. 37, pp. 4130-4146, 1994. https://doi.org/10.1021/jm00050a010
  18. S. Wold, A. Ruhe, H. Wold, and W. J. Dunn, "The collinearity problem in linear-regression- the partial least squares (PLS) approach to generalized inverses", SIAM Journal on Scientific and Statistical Computing, Vol. 5, pp. 735-743, 1984. https://doi.org/10.1137/0905052
  19. S. Wold, "Cross-validatory estimation of the number of components in factor and principal component model", Technometrics, Vol. 20, pp. 397-405, 1978. https://doi.org/10.1080/00401706.1978.10489693