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Balancing focused combinatorial libraries based on multiple GPCR ligands

  • GPCR Symposium
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Abstract

G-Protein coupled receptors (GPCRs) are important targets for drug discovery, and combinatorial chemistry is an important tool for pharmaceutical development. The absence of detailed structural information, however, limits the kinds of combinatorial design techniques that can be applied to GPCR targets. This is particularly problematic given the current emphasis on focused combinatorial libraries. By linking an incremental construction method (OptDesign) to the very fast shape-matching capability of ChemSpace, we have created an efficient method for designing targeted sublibraries that are topomerically similar to known actives. Multi-objective scoring allows consideration of multiple queries (actives) simultaneously. This can lead to a distribution of products skewed towards one particular query structure, however, particularly when the ligands of interest are quite dissimilar to one another. A novel pivoting technique is described which makes it possible to generate promising designs even under those circumstances. The approach is illustrated by application to some serotonergic agonists and chemokine antagonists.

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Abbreviations

5HT1F :

5-Hydroxytryptamine (serotonin) receptor, subtype 1F

Boc:

tert-Butoxycarbonyl

CCR1:

Chemotactic cytokine receptor 1

GPCR:

G-protein coupled receptor

References

  1. Filmore D (2004) Mod Drug Discov 11:24

    Google Scholar 

  2. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Science 289:739

    Article  CAS  Google Scholar 

  3. Krier M, de Araújo-Júnior JX, Schmitt M, Duranton J, Justiano-Basaran H, Lugnier C., Bouruignon J-J, Rognan D (2005) J Med Chem 48:3816

    Article  CAS  Google Scholar 

  4. OptDesign® is distributed by Tripos, Inc., 1699 S. Hanley Road, St. Louis, MO 63144, USA (http://www.tripos.com)

  5. Clark RD, Patterson DE, Soltanshahi F, Blake JF, Matthew JB (2000) J Mol Graph Model 18:404

    Article  CAS  Google Scholar 

  6. Clark RD (1997) J Chem Inf Comput Sci 37:1181

    Article  CAS  Google Scholar 

  7. Clark RD, Langton WJ (1998) J Chem Inf Comput Sci 38:1079

    Article  CAS  Google Scholar 

  8. Clark RD, US Patent No. 6,535,819 (2003) OptiSim™ is licensed by Tripos, Inc., 1699 S. Hanley Road, St. Louis, MO 63144, USA (http://www.tripos.com)

  9. Clark RD, Kar J, Akella L, Soltanshahi F (2003) J Chem Inf Comput Sci 43:829

    Article  CAS  Google Scholar 

  10. Gillet VJ, Willett P, Fleming PJ, Green DVS (2002) J Mol Graph Model 20:491

    Article  CAS  Google Scholar 

  11. Patterson DE, Cramer RD, Ferguson AM, Clark RD, Weinberger LE (1996) J Med Chem 39:3049

    Article  CAS  Google Scholar 

  12. Cramer RD, Poss MA, Hermsmeier MA, Caulfield TJ, Kowala MC, Valentine MT (1999) J Med Chem 42:3919

    Article  CAS  Google Scholar 

  13. Pauwels PJ, 5-HT Receptors and Their Ligands, www.tocris.com

  14. Horuk R, Ng HP, (2000) Med Res Rev 20:155

    Article  CAS  Google Scholar 

  15. Lüttichau HR, Schwartz TW, (2000) Drug Discov Dev 3:610

    Google Scholar 

  16. Kaplan AP (2001) Int Arch Allergy Immunol 124:423

    Article  CAS  Google Scholar 

  17. Lainton JAH, Allen MC, Burton M, Cameron S, Edwards TRG, Harden G, Hogg R, Leung W, Miller S, Morrish JJ, Rooke SM, Wendt B (2003) J Comb Chem 5:400

    Article  CAS  Google Scholar 

  18. ChemSpace® is licensed by Tripos, Inc., 1699 S. Hanley Road, St. Louis, MO 63144, USA (http://www.tripos.com); Cramer, R.D. and Patterson, D.E., US Patent No. 6,240,374 (2001)

  19. Cramer RD, Patterson DE, Clark RD, Soltanshahi F, Lawless MS (1998) J Chem Inf Comp Sci 6:1010

    Article  Google Scholar 

  20. Andrews KM, Cramer RD (2000) J Med Chem 43:1723

    Article  CAS  Google Scholar 

  21. Cramer RD, Jilek RJ, Guessregen S, Clark SJ, Wendt B, Clark RD (2004) J Med Chem 47:6777

    Article  CAS  Google Scholar 

  22. ClogP is a product of BioByte Inc., Pomona CA

  23. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Adv Drug Del Rev 23:4

    Article  Google Scholar 

  24. Ash S, Cline MA, Homer RW, Hurst T, Smith GB (1997) J Chem Inf Comput Sci 37:71

    Article  CAS  Google Scholar 

  25. Integer arithmetic is used, so 50% of 3 is 2

  26. Waly MA (2000) Boll Chim Farm 139:217

    CAS  Google Scholar 

  27. Xu Y-C, Johnson KW, Phebus LA, Cohen M, Nelson DL, Schenck K, Walker CD, Fritz JE, Kaldor SW, Le Tourneau ME, Murff RE, Zgombick JM, Calligaro DO, Audia JE, Schaus JM (2001) J Med Chem 44:4031

    Article  CAS  Google Scholar 

  28. Fritz JE, Kaldor SW, Liang SX, Singh U, Xu Y-C (1998) Internatl. Patent No. WO9815545

  29. Roland C, Gozalbes R, Nicolai E, Paugam M-F, Coussy L, Barbosa F, Horvath D, Revah F (2005) J Med Chem 48:6563

    Article  CAS  Google Scholar 

  30. Pennell AMK, Aggen JB, Wright JJK, Sen S, McMaster BE, Dairaghi DJ (2003) Internatl. Patent No.WO03105853

  31. Bauman JG, Buckman BO, Ghanam AF, Hesselgesser JE, Horuk R, Islam I, Liang M, May KB, Monahan SD, Morissey MM, Ng HP, Wei GP, Xu W, Zheng W (1998) Internatl. Patent No. WO9856771

  32. Wellner E, Sandin H (2005) Internatl. Patent No. WO05080362

  33. McMaster B (2003) Internatl. Patent No. WO03105857

  34. Sprous DG, Lowis DR, Leonard JM, Heritage T, Burkett SN, Baker DS, Clark RD (2004) J Comb Chem 6:530

    Article  CAS  Google Scholar 

  35. LeadDiscovery™ screening libraries are distributed by Tripos, Inc., 1699 S. Hanley Rd., St. Louis, MO 63144, USA (http://www.tripos.com)

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Acknowledgements

The authors would like to thank Dick Cramer, Mike Lawless, Jon Swanson and Rob Jilek of Tripos, Inc., for their support and many helpful discussions about ChemSpace.

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Author notes

  1. Sun Choi

    Present address: College of Pharmacy and Division of Molecular Life Sciences, Ewha Womans University, Seoul, 120-750, South Korea

Authors and Affiliations

  1. Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, St Louis, MO, 63144, USA

    Farhad Soltanshahi, Tamsin E. Mansley, Sun Choi & Robert D. Clark

Authors
  1. Farhad Soltanshahi
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  2. Tamsin E. Mansley
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  3. Sun Choi
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  4. Robert D. Clark
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Corresponding author

Correspondence to Robert D. Clark.

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Soltanshahi, F., Mansley, T.E., Choi, S. et al. Balancing focused combinatorial libraries based on multiple GPCR ligands. J Comput Aided Mol Des 20, 529–538 (2006). https://doi.org/10.1007/s10822-006-9076-9

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  • DOI: https://doi.org/10.1007/s10822-006-9076-9

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