Skip to main content

Advertisement

Springer Nature Link
Log in

Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (structurally related to SB203580) and a set of decoy compounds. Multiple protonation states and tautomers of active and decoy compounds were considered. Each docking model was evaluated using receiver operating characteristic (ROC) curves and enrichment factors. The two best performing single crystal structures were found to be 1BL7 and 2EWA, with enrichment factors of 14.1 and 13.0 at 2 % of the virtual screen respectively. Ensembles of up to four receptors of similar conformations were generated, generally giving good or very good performances with high ROC AUCs and good enrichment. The 1BL7-2EWA ensemble was able to outperform each of its constituent receptors and gave high enrichment factors of 17.3, 12.0, 8.0 at 2, 5 and 10 % respectively, of the virtual screen. A ROC AUC of 0.94 was obtained for this ensemble. This method may be applied to other proteins where there are a large number of inhibitor classes with different binding site conformations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Schieven GL (2005) Curr Top Med Chem 5(10):921

    Article  CAS  Google Scholar 

  2. Keshet Y, Seger R (2010) Methods Mol Biol 661:3

    Article  CAS  Google Scholar 

  3. Yong HY, Koh MS, Moon A (2009) Expert Opin Investig Drugs 18(12):1893

    Article  CAS  Google Scholar 

  4. Cuenda A, Rousseau S (2007) Biochim Biophys Acta 1773(8):1358

    Article  CAS  Google Scholar 

  5. Pettus LH, Wurz RP (2008) Curr Top Med Chem 8(16):1452

    Article  CAS  Google Scholar 

  6. Wu B, Wang HL, Pettus L, Wurz RP, Doherty EM, Henkle B, McBride HJ, Saris CJM, Wong LM, Plant MH, Sherman L, Lee MR, Hsieh F, Tasker AS (2010) J Med Chem 53(17):6398

    Google Scholar 

  7. Dominguez C, Tamayo N, Zhang D (2005) Expert Opin Ther Pat 15(7):801

    Google Scholar 

  8. Jackson PF, Bullington JL (2002) Curr Top Med Chem 2(9):1011

    Article  CAS  Google Scholar 

  9. Trejo A, Arzeno H, Browner M, Chanda S, Cheng S, Comer DD, Dalrymple SA, Dunten P, Lafargue J, Lovejoy B, Freire-Moar J, Lim J, McIntosh J, Miller J, Papp E, Reuter D, Roberts R, Sanpablo F, Saunders J, Song K, Villasenor A, Warren SD, Welch M, Weller P, Whiteley PE, Zeng L, Goldstein DM (2003) J Med Chem 46(22):4702

    Article  CAS  Google Scholar 

  10. Goldstein DM, Gabriel T (2005) Curr Top Med Chem 5(10):1017

    Article  CAS  Google Scholar 

  11. Hynes J Jr, Leftheris K (2005) Curr Top Med Chem 5(10):967

    Google Scholar 

  12. Lee MR, Dominguez C (2005) Curr Med Chem 12(25):2979

    Article  CAS  Google Scholar 

  13. Tamayo N, Liao L, Goldberg M, Powers D, Tudor YY, Yu V, Wong LM, Henkle B, Middleton S, Syed R, Harvey T, Jang G, Hungate R, Dominguez C (2005) Bioorg Med Chem Lett 15(9):2409

    Article  CAS  Google Scholar 

  14. Peifer C, Wagner G, Laufer S (2006) Curr Top Med Chem 6(2):113

    Article  CAS  Google Scholar 

  15. Laufer SA, Hauser DRJ, Domeyer DM, Kinkel K, Liedtke AJ (2008) J Med Chem 51(14):4122

    Google Scholar 

  16. Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, Patel VK, Smee PA, Somers DO, Vitulli G, Walker AL (2009) J Med Chem 52(20):6257

    Article  CAS  Google Scholar 

  17. Selness SR, Devraj RV, Monahan JB, Boehm TL, Walker JK, Devadas B, Durley RC, Kurumbail R, Shieh H, Xing L, Hepperle M, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, Blevis-Bal R (2009) Bioorg Med Chem Lett 19(20):5851

    Article  CAS  Google Scholar 

  18. Goldstein DM, Kuglstatter A, Lou Y, Soth MJ (2010) J Med Chem 53(6):2345

    Article  CAS  Google Scholar 

  19. Mavunkel BJ, Perumattam JJ, Tan X, Luedtke GR, Lu Q, Lim D, Kizer D, Dugar S, Chakravarty S, Xu YJ, Jung J, Liclican A, Levy DE, Tabora J (2010) Bioorg Med Chem Lett 20(3):1059

    Article  CAS  Google Scholar 

  20. Wang Z, Harkins PC, Ulevitch RJ, Han J, Cobb MH, Goldsmith EJ (1997) Proc Natl Acad Sci USA 94(6):2327

    Google Scholar 

  21. Traxler P (1998) Expert Opin Ther Pat 8(12):1599

    Article  CAS  Google Scholar 

  22. Tong L, Pav S, White DM, Rogers S, Crane KM, Cywin CL, Brown ML, Pargellis CA (1997) Nat Struct Biol 4(4):311

    Article  CAS  Google Scholar 

  23. Angiolini M (2011) Future Med Chem 3(3):309

    Article  CAS  Google Scholar 

  24. Filomia F, De Rienzo F, Menziani MC (2010) Bioorg Med Chem 18(18):6805

    Article  CAS  Google Scholar 

  25. Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S, Regan J (2002) Nat Struct Biol 9(4):268

    Article  CAS  Google Scholar 

  26. Gill AL, Frederickson M, Cleasby A, Woodhead SJ, Carr MG, Woodhead AJ, Walker MT, Congreve MS, Devine LA, Tisi D, O'Reilly M, Seavers LCA, Davis DJ, Curry J, Anthony R, Padova A, Murray CW, Carr RAE, Jhoti H (2005) J Med Chem 48(2):414

    Google Scholar 

  27. Karcher SC, Laufer SA (2009) Curr Top Med Chem 9(7):655

    Article  CAS  Google Scholar 

  28. Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC (1995) FEBS Lett 364(2):229

    Article  CAS  Google Scholar 

  29. Hubbard RE (ed) (2006) Structure based drug discovery: an overview. The Royal Society of Chemistry, Cambridge

    Google Scholar 

  30. Wlodawer A, Minor W, Dauter Z, Jaskolski M (2008) FEBS J 275(1):1

    Article  CAS  Google Scholar 

  31. Acharya KR, Lloyd MD (2005) Trends Pharmacol Sci 26(1):10

    Article  CAS  Google Scholar 

  32. Andricopulo AD, Salum LB, Abraham DJ (2009) Curr Top Med Chem 9(9):771

    Article  CAS  Google Scholar 

  33. Cheeseright TJ, Holm M, Lehmann F, Luik S, Gottert M, Melville JL, Laufer S (2009) J Med Chem 52(14):4200

    Article  CAS  Google Scholar 

  34. Armen RS, Chen J, Brooks CL (2009) J Chem Theory Comput 5(10):2909

    Google Scholar 

  35. Rao S, Sanschagrin PC, Greenwood JR, Repasky MP, Sherman W, Farid R (2008) J Comput-Aided Mol Des 22(9):621

    Article  CAS  Google Scholar 

  36. Wang Z, Canagarajah BJ, Boehm JC, Kassisa S, Cobb MH, Young PR, Abdel-Meguid S, Adams JL, Goldsmith EJ (1998) Structure 6(9):1117

    Google Scholar 

  37. Shewchuk L, Hassell A, Wisely B, Rocque W, Holmes W, Veal J, Kuyper LF (2000) J Med Chem 43(1):133

    Article  CAS  Google Scholar 

  38. Stelmach JE, Liu L, Patel SB, Pivnichny JV, Scapin G, Singh S, Hop CECA, Wang Z, Strauss JR, Cameron PM, Nichols EA, O'Keefe SJ, O'Neill EA, Schmatz DM, Schwartz CD, Thompson CM, Zaller DM, Doherty JB (2003) Bioorg Med Chem Lett 13(2):277

    Google Scholar 

  39. Fitzgerald CE, Patel SB, Becker JW, Cameron PM, Zaller D, Pikounis VB, O’Keefe SJ, Scapin G (2003) Nat Struct Biol 10(9):764

    Article  CAS  Google Scholar 

  40. Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H (2005) J Med Chem 48(2):403

    Article  CAS  Google Scholar 

  41. Michelotti EL, Moffett KK, Nguyen D, Kelly MJ, Shetty R, Chai X, Northrop K, Namboodiri V, Campbell B, Flynn GA, Fujimoto T, Hollinger FP, Bukhtiyarova M, Springman EB, Karpusas M (2005) Bioorg Med Chem Lett 15(23):5274

    Article  CAS  Google Scholar 

  42. McClure KF, Abramov YA, Laird ER, Barberia JT, Cai W, Carty TJ, Cortina SR, Danley DE, Dipesa AJ, Donahue KM, Dombroski MA, Elliott NC, Gabel CA, Han S, Hynes TR, LeMotte PK, Mansour MN, Marr ES, Letavic MA, Pandit J, Ripin DB, Sweeney FJ, Tan D, Tao Y (2005) J Med Chem 48(18):5728

    Google Scholar 

  43. Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, Breeze AL, Bermingham A, Pauptit RA, Norman RA, Embrey KJ, Read J, VanScyoc WS, Ward WHJ (2005) Biochemistry 44(50):16475

    Google Scholar 

  44. Vogtherr M, Saxena K, Hoelder S, Grimme S, Betz M, Schieborr U, Pescatore B, Robin M, Delarbre L, Langer T, Wendt KU, Schwalbe H (2006) Angew Chem Int Ed Engl 45(6):993

    Article  CAS  Google Scholar 

  45. Angell R, Aston NM, Bamborough P, Buckton JB, Cockerill S, deBoeck SJ, Edwards CD, Holmes DS, Jones KL, Laine DI, Patel S, Smee PA, Smith KJ, Somers DO, Walker AL (2008) Bioorg Med Chem Lett 18(15):4428

    Article  CAS  Google Scholar 

  46. Cogan DA, Aungst R, Breinlinger EC, Fadra T, Goldberg DR, Hao MH, Kroe R, Moss N, Pargellis C, Qian KC, Swinamer AD (2008) Bioorg Med Chem Lett 18(11):3251

    Article  CAS  Google Scholar 

  47. Baldwin I, Bamborough P, Haslam CG, Hunjan SS, Longstaff T, Mooney CJ, Patel S, Quinn J, Somers DO (2008) Bioorg Med Chem Lett 18(19):5285

    Article  CAS  Google Scholar 

  48. Wurz RP, Pettus LH, Xu S, Henkle B, Sherman L, Plant M, Miner K, McBride H, Wong LM, Saris CJM, Lee MR, Chmait S, Mohr C, Hsieh F, Tasker AS (2009) Bioorg Med Chem Lett 19(16):4724

    Google Scholar 

  49. Simard JR, Getlik M, Grutter C, Schneider R, Wulfert S, Rauh D (2010) J Am Chem Soc 132(12):4152

    Article  CAS  Google Scholar 

  50. Jerome KD, Rucker PV, Xing L, Shieh HS, Baldus JE, Selness SR, Letavic MA, Braganza JF, McClure KF (2010) Bioorg Med Chem Lett 20(2):469

    Article  CAS  Google Scholar 

  51. Goldstein DM, Soth M, Gabriel T, Dewdney N, Kuglstatter A, Arzeno H, Chen J, Bingenheimer W, Dalrymple SA, Dunn J, Farrell R, Frauchiger S, La Fargue J, Ghate M, Graves B, Hill RJ, Li F, Litman R, Loe B, McIntosh J, McWeeney D, Papp E, Park J, Reese HF, Roberts RT, Rotstein D, San Pablo B, Sarma K, Stahl M, Sung ML, Suttman RT, Sjogren EB, Tan Y, Trejo A, Welch M, Weller P, Wong BR, Zecic H (2011) J Med Chem 54(7):2255

    Article  CAS  Google Scholar 

  52. Soth M, Abbot S, Abubakari A, Arora N, Arzeno H, Billedeau R, Dewdney N, Durkin K, Frauchiger S, Ghate M, Goldstein DM, Hill RJ, Kuglstatter A, Li F, Loe B, McCaleb K, McIntosh J, Papp E, Park J, Stahl M, Sung ML, Suttman R, Swinney DC, Weller P, Wong B, Zecic H, Gabriel T (2011) Bioorg Med Chem Lett 21(11):3452

    Article  CAS  Google Scholar 

  53. Down K, Bamborough P, Alder C, Campbell A, Christopher JA, Gerelle M, Ludbrook S, Mallett D, Mellor G, Miller DD, Pearson R, Ray K, Solanke Y, Somers D (2010) Bioorg Med Chem Lett 20(13):3936

    Article  CAS  Google Scholar 

  54. Ahn YM, Clare M, Ensinger CL, Hood MM, Lord JW, Lu WP, Miller DF, Patt WC, Smith BD, Vogeti L, Kaufman MD, Petillo PA, Wise SC, Abendroth J, Chun L, Clark R, Feese M, Kim H, Stewart L, Flynn DL (2010) Bioorg Med Chem Lett 20(19):5793

    Article  CAS  Google Scholar 

  55. Lin S, Wrobleski ST, Hynes J Jr, Pitt S, Zhang R, Fan Y, Doweyko AM, Kish KF, Sack JS, Malley MF, Kiefer SE, Newitt JA, McKinnon M, Trzaskos J, Barrish JC, Dodd JH, Schieven GL, Leftheris K (2010) Bioorg Med Chem Lett 20(19):5864

    Article  CAS  Google Scholar 

  56. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28(1):235

    Article  CAS  Google Scholar 

  57. Wagner G, Laufer S (2006) Med Res Rev 26(1):1

    Article  CAS  Google Scholar 

  58. 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(7):1739

    Article  CAS  Google Scholar 

  59. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) J Med Chem 47(7):1750

    Article  CAS  Google Scholar 

  60. McRobb FM, Capuano B, Crosby IT, Chalmers DK, Yuriev E (2010) J Chem Inf Model 50(4):626

    Article  CAS  Google Scholar 

  61. Daylight Chemical Information Systems, Inc. http://www.daylight.com/dayhtml/doc/theory/theory.smarts.html Accessed 21 Nov 2011

  62. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) J Med Chem 49(21):6177

    Article  CAS  Google Scholar 

  63. Triballeau N, Acher F, Brabet I, Pin J-P, Bertrand H-O (2005) J Med Chem 48(7):2534

    Article  CAS  Google Scholar 

  64. Pearlman DA, Charifson PS (2001) J Med Chem 44(4):502

    Article  CAS  Google Scholar 

  65. Adams JL, Boehm JC, Gallagher TF, Kassis S, Webb EF, Hall R, Sorenson M, Garigipati R, Griswold DE, Lee JC (2001) Bioorg Med Chem Lett 11(21):2867

    Article  CAS  Google Scholar 

  66. Boehm JC, Bower MJ, Gallagher TF, Kassis S, Johnson SR, Adams JL (2001) Bioorg Med Chem Lett 11(9):1123

    Article  CAS  Google Scholar 

  67. Boehm JC, Smietana JM, Sorenson ME, Garigipati RS, Gallagher TF, Sheldrake PL, Bradbeer J, Badger AM, Laydon JT, Lee JC, Hillegass LM, Griswold DE, Breton JJ, Chabot-Fletcher MC, Adams JL (1996) J Med Chem 39(20):3929

    Article  CAS  Google Scholar 

  68. Gallagher TF, Seibel GL, Kassis S, Laydon JT, Blumenthal MJ, Lee JC, Lee D, Boehm JC, Fier-Thompson SM, Abt JW, Soreson ME, Smietana JM, Hall RF, Garigipati RS, Bender PE, Erhard KF, Krog AJ, Hofmann GA, Sheldrake PL, McDonnell PC, Kumar S, Young PR, Adams JL (1997) Bioorg Med Chem 5(1):49

    Article  CAS  Google Scholar 

  69. Gallagher TF, Fier-Thompson SM, Garigipati RS, Sorenson ME, Smietana JM, Lee D, Bender PE, Lee JC, Laydon JT, Griswold DE, Chabot-Fletcher MC, Breton JJ, Adams JL (1995) Bioorg Med Chem Lett 5(11):1171

    Article  CAS  Google Scholar 

  70. Thurmond RL, Wadsworth SA, Schafer PH, Zivin RA, Siekierka JJ (2001) Eur J Biochem 268(22):5747

    Article  CAS  Google Scholar 

  71. Laufer SA, Striegel HG, Wagner GK (2002) J Med Chem 45(21):4695

    Article  CAS  Google Scholar 

  72. de Laszlo SE, Visco D, Agarwal L, Chang L, Chin J, Croft G, Forsyth A, Fletcher D, Frantz B, Hacker C, Hanlon W, Harper C, Kostura M, Li B, Luell S, MacCoss M, Mantlo N, O'Neill EA, Orevillo C, Pang M, Parsons J, Rolando A, Sahly Y, Sidler K, Widmer WR, O'Keefe SJ (1998) Bioorg Med Chem Lett 8(19):2689

    Google Scholar 

  73. Revesz L, Blum E, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Rucklin G (2004) Bioorg Med Chem Lett 14(13):3595

    Article  CAS  Google Scholar 

  74. Revesz L, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Wolf R, Zimmerlin AG (2002) Bioorg Med Chem Lett 12(16):2109

    Article  CAS  Google Scholar 

  75. Revesz L, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Zimmerlin AG (2000) Bioorg Med Chem Lett 10(11):1261

    Article  CAS  Google Scholar 

  76. Fujita M, Hirayama T, Ikeda N (2002) Bioorg Med Chem 10(10):3113

    Article  CAS  Google Scholar 

  77. Laufer SA, Wagner GK (2002) J Med Chem 45(13):2733

    Article  CAS  Google Scholar 

  78. Rupert KC, Henry JR, Dodd JH, Wadsworth SA, Cavender DE, Olini GC, Fahmy B, Siekierka JJ (2003) Bioorg Med Chem Lett 13(3):347

    Article  CAS  Google Scholar 

  79. Leach AR, Shoichet BK, Peishoff CE (2006) J Med Chem 49(20):5851

    Article  CAS  Google Scholar 

  80. Craig IR, Essex JW, Spiegel K (2010) J Chem Inf Model 50(4):511

    Article  CAS  Google Scholar 

Download references

Acknowledgments

N. B. Vinh is supported by an Australian Postgraduate Award (APA) scholarship. The authors acknowledge computational resources and technical support provided by Victorian Partnership for Advanced Computing (VPAC).

Author information

Authors and Affiliations

  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, 3052, Australia

    Natalie B. Vinh, Jamie S. Simpson, Peter J. Scammells & David K. Chalmers

Authors
  1. Natalie B. Vinh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jamie S. Simpson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter J. Scammells
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David K. Chalmers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David K. Chalmers.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1347 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vinh, N.B., Simpson, J.S., Scammells, P.J. et al. Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK. J Comput Aided Mol Des 26, 409–423 (2012). https://doi.org/10.1007/s10822-012-9569-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-012-9569-7

Keywords