Journal of Computer-Aided Molecular Design

, Volume 26, Issue 11, pp 1217–1228 | Cite as

Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

  • Ori Kalid
  • Dora Toledo Warshaviak
  • Sharon Shechter
  • Woody Sherman
  • Sharon Shacham
Article

Abstract

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.

Keywords

Docking Virtual screening Structure-based drug design Induced Fit Docking Receptor flexibility Crm1 Exportin-1 Nuclear transport 

Supplementary material

10822_2012_9611_MOESM1_ESM.docx (13.1 mb)
Supplementary material 1 (DOCX 13399 kb)

References

  1. 1.
    Tsou CL (1993) Science 262(5132):380CrossRefGoogle Scholar
  2. 2.
    Teague SJ (2003) Nat Rev Drug Disc 2(7):527CrossRefGoogle Scholar
  3. 3.
    Carlson HA, McCammon JA (2000) Mol Pharmacol 57(2):213Google Scholar
  4. 4.
    Carlson HA (2002) Curr Opin Chem Biol 6(4):447CrossRefGoogle Scholar
  5. 5.
    Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) J Med Chem 49(21):6177CrossRefGoogle Scholar
  6. 6.
    Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) J Med Chem 47(7):1750CrossRefGoogle Scholar
  7. 7.
    Shoichet BK (2004) Nature 432(7019):862CrossRefGoogle Scholar
  8. 8.
    Shen J, Tan C, Zhang Y, Li X, Li W, Huang J, Shen X, Tang Y (2010) J Med Chem 53(14):5361CrossRefGoogle Scholar
  9. 9.
    Podvinec M, Lim SP, Schmidt T, Scarsi M, Wen D, Sonntag L-S, Sanschagrin P, Shenkin PS, Schwede T (2010) J Med Chem 53(4):1483CrossRefGoogle Scholar
  10. 10.
    Huggins DJ, Sherman W, Tidor B (2012) J Med Chem 55(4):1424CrossRefGoogle Scholar
  11. 11.
    Shan Y, Kim E, Eastwood MP, Dror RO, Seeliger MA, Shaw DE (2011) J Am Chem Soc 133(24):9181CrossRefGoogle Scholar
  12. 12.
    Gervasio FL, Laio A, Parrinello M (2005) J Am Chem Soc 127(8):2600CrossRefGoogle Scholar
  13. 13.
    Sherman W, Beard HS, Farid R (2006) Chem Biol Drug Des 67(1):83CrossRefGoogle Scholar
  14. 14.
    Huang SY, Zou X (2007) Proteins: Struct, Funct, Bioinf 66(2):399CrossRefGoogle Scholar
  15. 15.
    Rao S, Sanschagrin PC, Greenwood JR, Repasky MP, Sherman W, Farid R (2008) J Comput Aided Mol Des 22(9):621CrossRefGoogle Scholar
  16. 16.
    Barril X, Morley SD (2005) J Med Chem 48(13):4432CrossRefGoogle Scholar
  17. 17.
    Craig IR, Essex JW, Spiegel K (2010) J Chem Inf Model 50(4):511CrossRefGoogle Scholar
  18. 18.
    Bouzida D, Rejto PA, Arthurs S, Colson AB, Freer ST, Gehlhaar DK, Larson V, Luty BA, Rose PW, Verkhivker GM (1999) Int J Quantum Chem 72(1):73CrossRefGoogle Scholar
  19. 19.
    Rueda M, Bottegoni G, Abagyan R (2009) J Chem Inf Model 49(3):716CrossRefGoogle Scholar
  20. 20.
    Cavasotto CN, Kovacs JA, Abagyan RA (2005) J Am Chem Soc 127(26):9632CrossRefGoogle Scholar
  21. 21.
    Nichols SE, Baron R, Ivetac A, McCammon JA (2011) J Chem Inf Model 51(6):1439CrossRefGoogle Scholar
  22. 22.
    Osguthorpe DJ, Sherman W, Hagler AT (2012) J Phys Chem B 116(23):6952CrossRefGoogle Scholar
  23. 23.
    Osguthorpe DJ, Sherman W, Hagler AT (2012) Chem Biol Drug Des 80(2):182CrossRefGoogle Scholar
  24. 24.
    Corbeil CR, Englebienne P, Yannopoulos CG, Chan L, Das SK, Bilimoria D, L’Heureux L, Moitessier N (2008) J Chem Inf Model 48(4):902CrossRefGoogle Scholar
  25. 25.
    Cavasotto CN, Abagyan RA (2004) J Mol Biol 337(1):209CrossRefGoogle Scholar
  26. 26.
    Sela I, Golan G, Strajbl M, Rivenzon-Segal D, Bar-Haim S, Bloch I, Inbal B, Shitrit A, Ben-Zeev E, Fichman M, Markus Y, Marantz Y, Senderowitz H, Kalid O (2010) Curr Top Med Chem 10(6):638CrossRefGoogle Scholar
  27. 27.
    Roitberg A, Elber R (1991) J Chem Phys 95:9277CrossRefGoogle Scholar
  28. 28.
    Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) J Med Chem 49(2):534CrossRefGoogle Scholar
  29. 29.
    Kutay U, Güttinger S (2005) Trends Cell Biol 15(3):121CrossRefGoogle Scholar
  30. 30.
    Turner JG, Sullivan DM (2008) Curr Med Chem 15(26):2648CrossRefGoogle Scholar
  31. 31.
    Mutka SC, Yang WQ, Dong SD, Ward SL, Craig DA, Timmermans PBMWM, Murli S (2009) Cancer Res 69(2):510CrossRefGoogle Scholar
  32. 32.
    Köster M, Lykke-Andersen S, Elnakady YA, Gerth K, Washausen P, Höfle G, Sasse F, Kjems J, Hauser H (2003) Exp Cell Res 286(2):321CrossRefGoogle Scholar
  33. 33.
    Meissner T, Krause E, Vinkemeier U (2004) FEBS Lett 576(1):27CrossRefGoogle Scholar
  34. 34.
    Bonazzi S, Eidam O, Güttinger S, Wach J-Y, Zemp I, Kutay U, Gademann K (2010) J Am Chem Soc 132(4):1432CrossRefGoogle Scholar
  35. 35.
    Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA (2003) Cancer Cell 4(6):463CrossRefGoogle Scholar
  36. 36.
    Van Neck T, Pannecouque C, Vanstreels E, Stevens M, Dehaen W, Daelemans D (2008) Bioorg Med Chem 16(21):9487CrossRefGoogle Scholar
  37. 37.
    Shacham S, Kauffman M, Sandanayaka VP, Shechter S, US 2011/0275607 A1 (2011) Nuclear transport modulators and uses thereof. Google PatentsGoogle Scholar
  38. 38.
    Sakakibara K, Saito N, Sato T, Suzuki A, Hasegawa Y, Friedman JM, Kufe DW, VonHoff DD, Iwami T, Kawabe T (2011) Blood 118(14):3922CrossRefGoogle Scholar
  39. 39.
    McGaughey GB, Sheridan RP, Bayly CI, Culberson JC, Kreatsoulas C, Lindsley S, Maiorov V, Truchon J-F, Cornell WD (2007) J Chem Inf Model 47(4):1504CrossRefGoogle Scholar
  40. 40.
    Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, iyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996) Nature 384(6610):644CrossRefGoogle Scholar
  41. 41.
    Kiefer JR, Pawlitz JL, Moreland KT, Stegeman RA, Hood WF, Gierse JK, Stevens AM, Goodwin DC, Rowlinson SW, Marnett LJ, Stallings WC, Kurumbail RG (2000) Nature 405(6782):97CrossRefGoogle Scholar
  42. 42.
    Wang JL, Limburg D, Graneto MJ, Springer J, Hamper JRB, Liao S, Pawlitz JL, Kurumbail RG, Maziasz T, Talley JJ, Kiefer JR, Carter J (2010) Bioorg Med Chem Lett 20(23):7159CrossRefGoogle Scholar
  43. 43.
    Canvas v1.4. (2011) Schrödinger Inc., PortlandGoogle Scholar
  44. 44.
    Sastry M, Lowrie JF, Dixon SL, Sherman W (2010) J Chem Inf Model 50(5):771CrossRefGoogle Scholar
  45. 45.
    Das K, Lewi PJ, Hughes SH, Arnold E (2005) Prog Biophys Mol Biol 88(2):209CrossRefGoogle Scholar
  46. 46.
    Hopkins AL, Ren J, Milton J, Hazen RJ, Chan JH, Stuart DI, Stammers DK (2004) J Med Chem 47(24):5912CrossRefGoogle Scholar
  47. 47.
    Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S (2002) Nat Struct Mol Biol 9(4):268CrossRefGoogle Scholar
  48. 48.
    Etchin J, Sun Q, Kentsis A, Farmer A, Zhang Z, Sanda T, Mansour M, Barcelo C, McCauley D, Kauffman M (2012) Leukemia. doi:10.1038/leu.2012.219
  49. 49.
    Monecke T, Güttler T, Neumann P, Dickmanns A, Görlich D, Ficner R (2009) Science 324(5930):1087CrossRefGoogle Scholar
  50. 50.
    Khanna IK, Weier RM, Yu Y, Xu XD, Koszyk FJ, Collins PW, Koboldt CM, Veenhuizen AW, Perkins WE, Casler JJ, Masferrer JL, Zhang YY, Gregory SA, Seibert K, Isakson PC (1997) J Med Chem 40(11):1634CrossRefGoogle Scholar
  51. 51.
    Halgren T (2007) Chem Biol Drug Des 69(2):146CrossRefGoogle Scholar
  52. 52.
    Halgren T (2009) J Chem Inf Model 49:377CrossRefGoogle Scholar
  53. 53.
    Maestro v9.2. (2011) Schrödinger, Inc., PortlandGoogle Scholar
  54. 54.
    LigPrep v2.4. (2010) Schrödinger Inc., PortlandGoogle Scholar
  55. 55.
    Rogers D, Hahn M (2010) J Chem Inf Model 50(5):742CrossRefGoogle Scholar
  56. 56.
    Butina D (1999) J Chem Inf Comput Sci 39(4):747CrossRefGoogle Scholar
  57. 57.
    Prime v3.0. (2011) Schrödinger Inc., PortlandGoogle Scholar
  58. 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):1739CrossRefGoogle Scholar
  59. 59.
    Truchon J-F, Bayly CI (2007) J Chem Inf Model 47(2):488CrossRefGoogle Scholar
  60. 60.
    Salam NK, Nuti R, Sherman W (2009) J Chem Inf Model 49(10):2356CrossRefGoogle Scholar
  61. 61.
    Wang R, Lai L, Wang S (2002) J Comput Aided Mol Des 16(1):11CrossRefGoogle Scholar
  62. 62.
    Sastry M, Dixon S, Sherman W (2011) J Chem Inf Model 51(10):2455CrossRefGoogle Scholar
  63. 63.
    QikProp v2.0. (2011) Schrödinger Inc., PortlandGoogle Scholar
  64. 64.
    Daylight Chemical Information Systems (2008) Aliso ViejoGoogle Scholar
  65. 65.
    Portevin B, Tordjman C, Pastoureau P, Bonnet J, De Nanteuil G (2000) J Med Chem 43(24):4582CrossRefGoogle Scholar
  66. 66.
    Janusz JM, Young PA, Ridgeway JM, Scherz MW, Enzweiler K, Wu LI, Gan L, Chen J, Kellstein DE, Green SA, Tulich JL, Rosario-Jansen T, Magrisso IJ, Wehmeyer KR, Kuhlenbeck DL, Eichhold TH, Dobson RLM (1998) J Med Chem 41(18):3515CrossRefGoogle Scholar
  67. 67.
    Huang H-C, Li JJ, Garland DJ, Chamberlain TS, Reinhard EJ, Manning RE, Seibert K, Koboldt CM, Gregory SA, Anderson GD, Veenhuizen AW, Zhang Y, Perkins WE, Burton EG, Cogburn JN, Isakson PC, Reitz DB (1996) J Med Chem 39(1):253CrossRefGoogle Scholar
  68. 68.
    Motakis D, Parniak MA (2002) Antimicrob Agents Chemother 46(6):1851CrossRefGoogle Scholar
  69. 69.
    Tanaka H, Takashima H, Ubasawa M, Sekiya K, Inouye N, Baba M, Shigeta S, Walker RT, De Clercq E, Miyasaka T (1995) J Med Chem 38(15):2860CrossRefGoogle Scholar
  70. 70.
    Ludovici DW, Kavash RW, Kukla MJ, Ho CY, Ye H, De Corte BL, Andries K, de Béthune M-P, Azijn H, Pauwels R, Moereels HEL, Heeres J, Koymans LMH, de Jonge MR, Van Aken KJA, Daeyaert FFD, Lewi PJ, Das K, Arnold E, Janssen PAJ (2001) Bioorg Med Chem Lett 11(17):2229CrossRefGoogle Scholar
  71. 71.
    Himmel DM, Das K, Clark AD, Hughes SH, Benjahad A, Oumouch S, Guillemont J, Coupa S, Poncelet A, Csoka I, Meyer C, Andries K, Nguyen CH, Grierson DS, Arnold E (2005) J Med Chem 48(24):7582CrossRefGoogle Scholar
  72. 72.
    Sun J, Meyers MJ, Fink BE, Rajendran R, Katzenellenbogen JA, Katzenellenbogen BS (1999) Endocrinology 140(2):800CrossRefGoogle Scholar
  73. 73.
    Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras D (2001) J Biol Chem 276(18):15059CrossRefGoogle Scholar
  74. 74.
    Blizzard TA, DiNinno F, Morgan Ii JD, Chen HY, Wu JY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Fitzgerald PMD, Sharma N, Li Y, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML (2005) Bioorg Med Chem Lett 15(1):107CrossRefGoogle Scholar
  75. 75.
    Dykstra KD, Guo L, Birzin ET, Chan W, Yang YT, Hayes EC, DaSilva CA, Pai L-Y, Mosley RT, Kraker B, Fitzgerald PMD, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML (2007) Bioorg Med Chem Lett 17(8):2322CrossRefGoogle Scholar
  76. 76.
    Richardson TI, Frank SA, Wang M, Clarke CA, Jones SA, Ying B-P, Kohlman DT, Wallace OB, Shepherd TA, Dally RD, Palkowitz AD, Geiser AG, Bryant HU, Henck JW, Cohen IR, Rudmann DG, McCann DJ, Coutant DE, Oldham SW, Hummel CW, Fong KC, Hinklin R, Lewis G, Tian H, Dodge JA (2007) Bioorg Med Chem Lett 17(13):3544CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Ori Kalid
    • 1
    • 2
  • Dora Toledo Warshaviak
    • 3
  • Sharon Shechter
    • 1
  • Woody Sherman
    • 3
  • Sharon Shacham
    • 1
  1. 1.Karyopharm TherapeuticsNatickUSA
  2. 2.Ori Kalid ConsultingPardes-HannaIsrael
  3. 3.Schrödinger Inc.New YorkUSA

Personalised recommendations