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Can we use docking and scoring for hit-to-lead optimization?

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Abstract

Docking and scoring is currently one of the tools used for hit finding and hit-to-lead optimization when structural information about the target is known. Docking scores have been found useful for optimizing ligand binding to reproduce experimentally observed binding modes. The question is, can docking and scoring be used reliably for hit-to-lead optimization? To illustrate the challenges of scoring for hit-to-lead optimization, the relationship of docking scores with experimentally determined IC50 values measured in-house were tested. The influences of the particular target, crystal structure, and the precision of the scoring function on the ability to differentiate between actives and inactives were analyzed by calculating the area under the curve of receiver operator characteristic curves for docking scores. It was found that for the test sets considered, MW and sometimes ClogP were as useful as GlideScores and no significant difference was observed between SP and XP scores for differentiating between actives and inactives. Interpretation by an expert is still required to successfully utilize docking and scoring in hit-to-lead optimization.

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References

  1. Gschwend DA, Good AC, Kuntz ID (1996) J Mol Recog 9:175

    Article  CAS  Google Scholar 

  2. Perola E, Walters WP, Charifson PS (2004) Proteins 56:235

    Article  CAS  Google Scholar 

  3. Muegge I, Rarey M (2001) In: Boyd DB, Lipkowitz KB (eds) Reviews in computational chemistry, vol 17. Wiley-VCH, New York, Ch 1, p 1

  4. Muegge I, Enyedy I (2003) In: Abraham D (ed) Burger’s medicinal chemistry 5th edn. vol 1. Wiley, New York, p 243

  5. Muegge I, Enyedy I (2004) In: Bultinck P, De Winter H, Langenaeker W, Tollenaere J (eds) Computational medicinal chemistry for drug discovery. Marcel Dekker Inc, New York, p 405

  6. Muegge I, Enyedy IJ (2004) Curr Med Chem 11:693

    Article  CAS  Google Scholar 

  7. Bissantz C, Folkers G, Rognan D (2000) J Med Chem 43:4759

    Article  CAS  Google Scholar 

  8. Kroemer RT (2003) Biochem Soc Trans 31:980

    Article  CAS  Google Scholar 

  9. Cotesta S, Giordanetto F, Trosset JY, Crivori P, Kroemer RT, Stouten PFW, Vulpetti A (2005) Proteins 60:629

    Article  CAS  Google Scholar 

  10. Stouten PFW, Kroemer RT (2006) Comprehensive Medicinal Chemistry II 4:255

    CAS  Google Scholar 

  11. Kroemer RT (2007) Curr Protein Pept Sci 8:312

    Article  CAS  Google Scholar 

  12. Wang R, Lu Y, Wang S (2003) J Med Chem 46:2287

    Article  CAS  Google Scholar 

  13. Smith R, Hubbard RE, Gschwend DA, Leach AR, Good AC (2003) J Mol Graphics Model 22:41

    Article  CAS  Google Scholar 

  14. Ferrara P, Gohlke H, Price DJ, Klebe G, Brooks CL III (2004) J Med Chem 47:3032

    Article  CAS  Google Scholar 

  15. Kontoyianni M, McClellan LM, Sokol GS (2004) J Med Chem 47:558

    Article  CAS  Google Scholar 

  16. Kontoyianni M, Sokol GS, McClellan LM (2005) J Comput Chem 26:11

    Article  CAS  Google Scholar 

  17. Cummings MD, DesJarlais RL, Gibbs AC, Mohan V, Jaeger EP (2005) J Med Chem 48:962

    Article  CAS  Google Scholar 

  18. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) J Med Chem 49:5912

    Article  CAS  Google Scholar 

  19. Zhou Z, Felts AK, Friesner RA, Levy RM (2007) J Chem Inf Model 47:1599

    Article  CAS  Google Scholar 

  20. McGaughey GB, Sheridan RP, Bayly CI, Culberson JC, Kreatsoulas C, Lindsley S, Maiorov V, Truchon JF, Cornell WD (2007) J Chem Inf Model 47:1504

    Article  CAS  Google Scholar 

  21. Vangrevelinghe E, Zimmermann K, Schoepfer J, Portmann R, Fabbro D, Furet P (2003) J Med Chem 46:2656

    Article  CAS  Google Scholar 

  22. Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X, Huang Y, Long Y-Q, Roller P, Yang D, Wang S (2001) J Med Chem 44:4313

    Article  CAS  Google Scholar 

  23. Enyedy IJ, Lee S-L, Kuo AH, Dickson RB, Lin C-Y, Wang S (2001) J Med Chem 44:1349

    Article  CAS  Google Scholar 

  24. Tirado-Rives J, Jorgensen WL (2006) J Med Chem 49:5880

    Article  CAS  Google Scholar 

  25. Leach AR, Shoichet BK, Peishoff CE (2006) J Med Chem 49:5851

    Article  CAS  Google Scholar 

  26. Bytheway I, Cochran S (2004) J Med Chem 47:1683

    Article  CAS  Google Scholar 

  27. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) J Med Chem 49:6177

    Article  CAS  Google Scholar 

  28. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindialov IN, Bourne PE (2000) Nucleic Acids Res 28:235

    Article  CAS  Google Scholar 

  29. Miyazaki Y, Matsunaga S, Tang J, Maeda Y, Nakano M, Philippe RJ, Shibahara M, Liu W, Sato H, Wang L, Nolte RT (2005) Bioorg Med Chem Lett 15:2203

    Article  CAS  Google Scholar 

  30. Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H (2007) J Med Chem 50:611

    Article  CAS  Google Scholar 

  31. Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble MEM (2001) Structure 9:389

    Article  CAS  Google Scholar 

  32. Brown NR, Noble ME, Endicott JA, Johnson LN (1999) Nat Cell Biol 1:438

    Article  CAS  Google Scholar 

  33. Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Cancer Res 62:4236

    CAS  Google Scholar 

  34. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) J Med Chem 47:1739

    Article  CAS  Google Scholar 

  35. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) J Med Chem 47:1750

    Article  CAS  Google Scholar 

  36. Maestro, version 8.0.110, (2007) Schrodinger LLC, New York

  37. LigPrep, version 1.2, (2007) Schrodinger LLC, New York

  38. MacroModel, version 9.5.213, (2007) Schrodinger LLC, New York

  39. Still WC, Tempczyk A, Hawley RC, Hendrickson T (1990) J Am Chem Soc 112:6127

    Article  CAS  Google Scholar 

  40. Triballeau N, Acher F, Brabet I, Pin JP, Bertrand HO (2005) J Med Chem 48:2534

    Article  CAS  Google Scholar 

  41. Kornev AP, Haste NM, Taylor SS, Ten Eyck LF (2006) Proc Natl Acad Sci USA 103:17783

    Article  CAS  Google Scholar 

  42. Tirado-Rives J, Jorgensen WL (2006) J Med Chem 49:5880

    Article  CAS  Google Scholar 

  43. Pearlman DA, Charifson PS (2001) J Med Chem 44:3417

    Article  CAS  Google Scholar 

  44. Triballeau N, Acher F, Brabet I, Pin JP, Bertrand HO (2005) J Med Chem 48:2534

    Article  CAS  Google Scholar 

  45. Hanley JA, McNeil BJ (1982) Radiology 143:29

    CAS  Google Scholar 

  46. Verma S, Nagarathnam D, Shao J, Zhang L, Zhao J, Wang Y, Li T, Mull E, Enyedy I, Wang C, Zhu Q, Altieri M, Jordan J, Dang TTA, Reddy S (2005) Bioorg Med Chem Lett 15:1973

    Article  CAS  Google Scholar 

  47. Page CS, Bates PA (2006) J Comput Chem 27:1990

    Article  CAS  Google Scholar 

  48. Coupez B, Lewis RA (2006) Curr Med Chem 13:2995

    Article  CAS  Google Scholar 

  49. Sheu SH, Kaya T, Waxman DJ, Vajda S (2005) Biochemistry 44:1193

    Article  CAS  Google Scholar 

  50. Prasad JC, Goldstone JV, Camacho CJ, Vajda S, Stegeman JJ (2007) Biochemistry 46:2640

    Article  CAS  Google Scholar 

  51. Wang J, Hou T, Xu X (2006) Curr Comput Aided Drug Des 2:287

    Article  CAS  Google Scholar 

  52. Xiong Y, Li Y, He H, Zhan CG (2007) Bioorg Med Chem Lett 17:5186

    Article  CAS  Google Scholar 

  53. Ferrari AM, Degliesposti G, Sgobba M, Rastelli G (2007) Bioorg Med Chem 15:7865

    Article  CAS  Google Scholar 

  54. Zhou Z, Bates M, Madura JD (2006) Proteins 65:580

    Article  CAS  Google Scholar 

  55. Lyne PD, Lamb ML, Saeh JC (2006) J Med Chem 49:4805

    Article  CAS  Google Scholar 

Download references

Acknowledgment

The authors thank Robert Pearlstein, Richard Lewis, and Hanneke Jansen for their reviews of the manuscript.

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Authors and Affiliations

  1. Global Discovery Chemistry, Computer-Aided Drug Discovery, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA

    Istvan J. Enyedy & William J. Egan

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  1. Istvan J. Enyedy
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  2. William J. Egan
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Correspondence to Istvan J. Enyedy.

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Enyedy, I.J., Egan, W.J. Can we use docking and scoring for hit-to-lead optimization?. J Comput Aided Mol Des 22, 161–168 (2008). https://doi.org/10.1007/s10822-007-9165-4

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  • DOI: https://doi.org/10.1007/s10822-007-9165-4

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