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Construction of 4D-QSAR Models for Use in the Design of Novel p38-MAPK Inhibitors

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Summary

The p38-mitogen-activated protein kinase (p38-MAPK) plays a key role in lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) and interleukin−1 (IL−1) release during the inflammatory process, emerging as an attractive target for new anti-inflammatory agents. Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis [Hopfinger et al., J. Am. Chem. Soc., 119 (1997) 10509] was applied to a series of 33 (a training set of 28 and a test set of 5) pyridinyl-imidazole and pyrimidinyl-imidazole inhibitors of p38-MAPK, with IC50 ranging from 0.11 to 2100 nM [Liverton et al., J. Med. Chem., 42 (1999) 2180]. Five thousand conformations of each analogue were sampled from a molecular dynamics simulation (MDS) during 50 ps at a constant temperature of 303 K. Each conformation was placed in a 2 Å grid cell lattice for each of three trial alignments. 4D-QSAR models were constructed by genetic algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by leave-one-out cross-validation technique. In the best models, with three to six terms, the adjusted cross-validated squared correlation coefficients, Q2adj, ranged from 0.67 to 0.85. Model D (Q2adj = 0.84) was identified as the most robust model from alignment 1, and it is representative of the other best models. This model encompasses new molecular regions as containing pharmacophore sites, such as the amino-benzyl moiety of pyrimidine analogs and the N1-substituent in the imidazole ring. These regions of the ligands should be further explored to identify better anti-inflammatory inhibitors of p38-MAPK.

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References

  1. R.C. Newton C.P. Decicco (1999) J. Med. Chem. 42 2295 Occurrence Handle10.1021/jm980541n Occurrence Handle10395470

    Article  PubMed  Google Scholar 

  2. W.P. Arend J.M. Dayer (1995) Arthritis Rheum. 38 151 Occurrence Handle7848304

    PubMed  Google Scholar 

  3. J. Raingeaud S. Gupta J.S. Rogers M. Dickens J. Han R.J. Ulevitch R.J. Davis (1995) J. Biol. Chem. 270 7420 Occurrence Handle10.1074/jbc.270.13.7420 Occurrence Handle7535770

    Article  PubMed  Google Scholar 

  4. J.C. Lee S. Kumar D.E. Griswold D.C. Underwood B.J. Votta J.L. Adams (2000) Immunopharmacology 47 185 Occurrence Handle10.1016/S0162-3109(00)00206-X Occurrence Handle10878289

    Article  PubMed  Google Scholar 

  5. K.K. Hale D. Trollinger M. Rihanek C.L. Manthey (1999) J. Immunol. 162 4246 Occurrence Handle10201954

    PubMed  Google Scholar 

  6. J. Han J.D. Lee Y. Jiang Z. Li L. Feng R.J. Ulevitch (1994) Science 265 808 Occurrence Handle7914033

    PubMed  Google Scholar 

  7. J.M. Kyriakis J. Avruch (1996) J. Biol. Chem. 271 24313 Occurrence Handle10.1074/jbc.271.40.24313 Occurrence Handle8798679

    Article  PubMed  Google Scholar 

  8. P. Cohen (1999) Curr. Opin. Chem. Biol. 3 459 Occurrence Handle10.1016/S1367-5931(99)80067-2 Occurrence Handle10419844

    Article  PubMed  Google Scholar 

  9. T.F. Gallagher G.L. Seibel S. Kassis J.T. Laydon M.J. Blumenthal D. Lee J.C. Boehm S.M. Thompson-Fier J.W. Abt M.E. Sorenson J.M. Smietana R.F. Hall R.S. Garigipati P.E. Bender K.F. Erhard A.J. Krog G.A. Hoffman P.L. Sheldrake P.C. McDonnell K.F. Kumar P.R. Young J.A. Adams (1997) Bioorg. Med. Chem. 5 49 Occurrence Handle10.1016/S0968-0896(96)00212-X Occurrence Handle9043657

    Article  PubMed  Google Scholar 

  10. J.C. Boehm M.J. Bower T.F. Gallagher S. Kassis S.R. Johnson J.L. Adams (2001) Bioorg. Med. Chem. Lett. 11 1123 Occurrence Handle10.1016/S0960-894X(01)00163-9 Occurrence Handle11354358

    Article  PubMed  Google Scholar 

  11. S.E. Laszlo Particlede D. Visco L. Agarwal L. Chang J. Chin G. Croft A. Forsyth D. Fletcher B. Frantz C. Hacker W. Hanlon C. Harper M. Kostura B. Li S. Luell M. MacCoss N. Mantlo E.A. O’Neill C. Orevillo M. Pang J. Parsons A. Rolando Y. Sahly K. Sidler S.J. O’Keefe (2000) Bioorg. Med. Chem. Lett. 8 2689 Occurrence Handle10.1016/S0960-894X(98)00495-8

    Article  Google Scholar 

  12. S. Mavel I. Thery A. Gueiffier (2002) Arch. Pharm. (Weinheim) 335 7 Occurrence Handle10.1002/1521-4184(200201)335:1<7::AID-ARDP7>3.0.CO;2-L

    Article  Google Scholar 

  13. A.M. Redman J.S. Johnson R. Dally S. Swartz H. Wild H. Paulsen Y. Caringal D. Gunn J. Renick M. Osterhout J. Kingery-Wood R.A. Smith W. Lee J. Dumas S.M. Wilhelm T.J. Housley A. Bhargava G.E. Ranges A. Shrikhande D. Young M. Bombara W.J. Scott (2001) Bioorg. Med. Chem. Lett. 11 9 Occurrence Handle10.1016/S0960-894X(00)00574-6 Occurrence Handle11140741

    Article  PubMed  Google Scholar 

  14. J.R. Henry K.C. Rupert J.H. Dodd I.J. Turchi S.A. Wadsworth D.E. Cavender P.H. Schafer J.J. Siekierka (1998) Bioorg. Med. Chem. Lett. 8 3335 Occurrence Handle10.1016/S0960-894X(98)00589-7 Occurrence Handle9873730

    Article  PubMed  Google Scholar 

  15. J.L. Adams J.C. Boehm S. Kassis P.D. Gorycki R. Hall M. Sorenson J.C. Lee A. Ayrton D.E. Griswold T.F. Gallagher (1998) Bioorg. Med. Chem. Lett. 8 3111 Occurrence Handle10.1016/S0960-894X(98)00549-6 Occurrence Handle9873686

    Article  PubMed  Google Scholar 

  16. N.J. Liverton J.W. Butcher C.F. Claiborne D.A. Claremon B.E. Libby K.T. Nguyen S.M. Pitzenberger H.G. Selnick G.R. Smith A. Tebben J.P. Vacca S.L. Varga L. Agarwal K. Dancheck A.J. Forsyth D.S. Fletcher B. Frantz W.A Hanlon C.F. Harper S.J. Hofsess M. Kostura J. Lin S. Luell E.A O’Neill C.J. Orevillo M. Pang J. Parsons A. Rolando Y. Sahly D.M. Visco S.J. O’Keefe (1999) J. Med. Chem. 42 2180 Occurrence Handle10.1021/jm9805236 Occurrence Handle10377223

    Article  PubMed  Google Scholar 

  17. L. Tong S. Pav D.A White S. Rogers K.M. Crane C.L. Cywin M.L. Brown C.A. Pargellis (1997) Nat. Struct. Biol. 4 311 Occurrence Handle10.1038/nsb0497-311 Occurrence Handle9095200

    Article  PubMed  Google Scholar 

  18. Z.L. Wang B.J. Canagarajah J.C. Boehm S. Kassisa M.H. Cobb P.R. Young S. Abdel-Meguid J.L. Adams E.J. Goldsmith (1998) Structure 6 1117 Occurrence Handle10.1016/S0969-2126(98)00113-0 Occurrence Handle9753691

    Article  PubMed  Google Scholar 

  19. S.P Gupta (2002) Prog. Drug Res. 58 223 Occurrence Handle12079201

    PubMed  Google Scholar 

  20. M. Akamatsu (2002) Curr. Top. Med. Chem. 2 1381 Occurrence Handle10.2174/1568026023392887 Occurrence Handle12470286

    Article  PubMed  Google Scholar 

  21. R. Bureau C. Daveu S. Lemaitre F. Dauphin H. Landelle J.C. Lancelot S. Rault (2002) J. Chem. Inf. Comput. Sci. 42 962 Occurrence Handle10.1021/ci0101354 Occurrence Handle12132898

    Article  PubMed  Google Scholar 

  22. H. Liu M. Ji X. Luo J. Shen X. Huang W. Hua H. Jiang K. Chen (2002) J. Med. Chem. 45 2953 Occurrence Handle10.1021/jm010574u Occurrence Handle12086482

    Article  PubMed  Google Scholar 

  23. M.G. Albuquerque A.J. Hopfinger E.J. Barreiro R.B. Alencastro Particlede (1998) J. Chem. Inf. Comput. Sci. 38 925 Occurrence Handle10.1021/ci980093s Occurrence Handle9770304

    Article  PubMed  Google Scholar 

  24. M. Ravi A.J. Hopfinger R.E. Hormann L. Dinan (2001) J. Chem. Inf. Comput. Sci. 41 1587 Occurrence Handle10.1021/ci010076u Occurrence Handle11749586

    Article  PubMed  Google Scholar 

  25. O.A. Santos-Filho A.J. Hopfinger (2001) J. Comp. Aided Mol. Des. 15 1 Occurrence Handle10.1023/A:1011152818340

    Article  Google Scholar 

  26. A.J. Hopfinger S. Wang J.S. Tokarski B. Jin M. Albuquerque P.J. Madhav C. Duraiswami (1997) J. Am. Chem. Soc. 119 10509 Occurrence Handle10.1021/ja9718937

    Article  Google Scholar 

  27. X. Hong A.J. Hopfinger (2003) J. Chem. Inf. Comput. Sci. 43 324 Occurrence Handle10.1021/ci0200321 Occurrence Handle12546568

    Article  PubMed  Google Scholar 

  28. M. Iyer R. Mishru Y. Han A. Hopfinger (2002) J. Pharm. Res. 19 1611 Occurrence Handle10.1023/A:1020792909928

    Article  Google Scholar 

  29. M.D. Krasowski X. Hong A.J. Hopfinger N.L. Harrison (2002) J. Med. Chem. 45 3210 Occurrence Handle10.1021/jm010461a Occurrence Handle12109905

    Article  PubMed  Google Scholar 

  30. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucleic Acids Res., 28 (2000) 235 (http://www.rcsb.org/pdb).

  31. Insight II User Guide (v.97.0), San Diego, MSI, 1997.

  32. M.J.S. Dewar E.G. Zoebisch E.F. Healy J.J.P. Stewart (1985) J. Am. Chem. Soc. 107 3902 Occurrence Handle10.1021/ja00299a024

    Article  Google Scholar 

  33. 4D-QSAR User’s Manual (v.1.00), The Chem21 Group Inc., 1780 Wilson Dr., Lake forest, IL 60045, 1997.

  34. MOLSIM User’s Guide (v.3.0), Doherty, D. C. and The Chem21 Group Inc., 1780 Wilson Dr., Lake Forest, IL 60045, 1997.

  35. S.J. Weiner P.A. Kollman D.T. Nguyen (1986) J. Comput. Chem. 7 230 Occurrence Handle10.1002/jcc.540070216

    Article  Google Scholar 

  36. D. Rogers A.J. Hopfinger (1989) J. Chem. Inf. Comput. Sci. 34 854 Occurrence Handle10.1021/ci00020a020

    Article  Google Scholar 

  37. Dunn III, W.J. and Rogers D., In Devillers J. (Ed.), Genetic Algorithms in Molecular Modeling. Academic Press, London, 1996.

  38. J.H. Friedman (1991) Ann. Stat. 19 1

    Google Scholar 

  39. Kubinyi H., In Mannhold R., Krogsgaard-Larsen P. and Timmerman H. (Eds.), Methods and Principles in Medicinal Chemistry, Vol. 1. VHC, Weinheim, 1993.

  40. D. Livingstone (1995) Data Analyses for Chemists: Applications to QSAR and Chemical Product Design Oxford University Press Inc New York

    Google Scholar 

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Authors and Affiliations

  1. Departamento de Química Orgânica, Laboratório de Modelagem Molecular (LabMMol), Instituto de Química, Centro de Tecnologia, Bloco A, Ilha do Fundão, Universidade Federal do Rio de Janeiro, 21949-900, Rio de Janeiro, RJ, Brasil

    Nelilma Correia Romeiro, Magaly Girão Albuquerque & Ricardo Bicca de Alencastro

  2. Department of Medicinal Chemistry and Pharmacognosy, Laboratory of Molecular Modeling and Design (LMMD), M/C 781, College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Illinois, Chicago, 60612-7231, USA

    Nelilma Correia Romeiro, Malini Ravi & Anton J. Hopfinger

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  1. Nelilma Correia Romeiro
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  2. Magaly Girão Albuquerque
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  3. Ricardo Bicca de Alencastro
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  5. Anton J. Hopfinger
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Correspondence to Nelilma Correia Romeiro.

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Romeiro, N.C., Albuquerque, M.G., de Alencastro, R.B. et al. Construction of 4D-QSAR Models for Use in the Design of Novel p38-MAPK Inhibitors. J Comput Aided Mol Des 19, 385–400 (2005). https://doi.org/10.1007/s10822-005-7927-4

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  • DOI: https://doi.org/10.1007/s10822-005-7927-4

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