Skip to main content

Advertisement

SpringerLink
Log in

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

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

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.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Tsou CL (1993) Science 262(5132):380

    Article  CAS  Google Scholar 

  2. Teague SJ (2003) Nat Rev Drug Disc 2(7):527

    Article  CAS  Google Scholar 

  3. Carlson HA, McCammon JA (2000) Mol Pharmacol 57(2):213

    CAS  Google Scholar 

  4. Carlson HA (2002) Curr Opin Chem Biol 6(4):447

    Article  CAS  Google Scholar 

  5. 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 

  6. 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 

  7. Shoichet BK (2004) Nature 432(7019):862

    Article  CAS  Google Scholar 

  8. Shen J, Tan C, Zhang Y, Li X, Li W, Huang J, Shen X, Tang Y (2010) J Med Chem 53(14):5361

    Article  CAS  Google Scholar 

  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):1483

    Article  CAS  Google Scholar 

  10. Huggins DJ, Sherman W, Tidor B (2012) J Med Chem 55(4):1424

    Article  CAS  Google Scholar 

  11. Shan Y, Kim E, Eastwood MP, Dror RO, Seeliger MA, Shaw DE (2011) J Am Chem Soc 133(24):9181

    Article  CAS  Google Scholar 

  12. Gervasio FL, Laio A, Parrinello M (2005) J Am Chem Soc 127(8):2600

    Article  CAS  Google Scholar 

  13. Sherman W, Beard HS, Farid R (2006) Chem Biol Drug Des 67(1):83

    Article  CAS  Google Scholar 

  14. Huang SY, Zou X (2007) Proteins: Struct, Funct, Bioinf 66(2):399

    Article  CAS  Google Scholar 

  15. 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 

  16. Barril X, Morley SD (2005) J Med Chem 48(13):4432

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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):73

    Article  CAS  Google Scholar 

  19. Rueda M, Bottegoni G, Abagyan R (2009) J Chem Inf Model 49(3):716

    Article  CAS  Google Scholar 

  20. Cavasotto CN, Kovacs JA, Abagyan RA (2005) J Am Chem Soc 127(26):9632

    Article  CAS  Google Scholar 

  21. Nichols SE, Baron R, Ivetac A, McCammon JA (2011) J Chem Inf Model 51(6):1439

    Article  CAS  Google Scholar 

  22. Osguthorpe DJ, Sherman W, Hagler AT (2012) J Phys Chem B 116(23):6952

    Article  CAS  Google Scholar 

  23. Osguthorpe DJ, Sherman W, Hagler AT (2012) Chem Biol Drug Des 80(2):182

    Article  CAS  Google Scholar 

  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):902

    Article  CAS  Google Scholar 

  25. Cavasotto CN, Abagyan RA (2004) J Mol Biol 337(1):209

    Article  CAS  Google Scholar 

  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):638

    Article  CAS  Google Scholar 

  27. Roitberg A, Elber R (1991) J Chem Phys 95:9277

    Article  CAS  Google Scholar 

  28. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) J Med Chem 49(2):534

    Article  CAS  Google Scholar 

  29. Kutay U, Güttinger S (2005) Trends Cell Biol 15(3):121

    Article  CAS  Google Scholar 

  30. Turner JG, Sullivan DM (2008) Curr Med Chem 15(26):2648

    Article  CAS  Google Scholar 

  31. Mutka SC, Yang WQ, Dong SD, Ward SL, Craig DA, Timmermans PBMWM, Murli S (2009) Cancer Res 69(2):510

    Article  CAS  Google Scholar 

  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):321

    Article  Google Scholar 

  33. Meissner T, Krause E, Vinkemeier U (2004) FEBS Lett 576(1):27

    Article  CAS  Google Scholar 

  34. Bonazzi S, Eidam O, Güttinger S, Wach J-Y, Zemp I, Kutay U, Gademann K (2010) J Am Chem Soc 132(4):1432

    Article  CAS  Google Scholar 

  35. Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA (2003) Cancer Cell 4(6):463

    Article  CAS  Google Scholar 

  36. Van Neck T, Pannecouque C, Vanstreels E, Stevens M, Dehaen W, Daelemans D (2008) Bioorg Med Chem 16(21):9487

    Article  Google Scholar 

  37. Shacham S, Kauffman M, Sandanayaka VP, Shechter S, US 2011/0275607 A1 (2011) Nuclear transport modulators and uses thereof. Google Patents

  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):3922

    Article  CAS  Google Scholar 

  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):1504

    Article  CAS  Google Scholar 

  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):644

    Article  CAS  Google Scholar 

  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):97

    Article  CAS  Google Scholar 

  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):7159

    Article  CAS  Google Scholar 

  43. Canvas v1.4. (2011) Schrödinger Inc., Portland

  44. Sastry M, Lowrie JF, Dixon SL, Sherman W (2010) J Chem Inf Model 50(5):771

    Article  CAS  Google Scholar 

  45. Das K, Lewi PJ, Hughes SH, Arnold E (2005) Prog Biophys Mol Biol 88(2):209

    Article  CAS  Google Scholar 

  46. Hopkins AL, Ren J, Milton J, Hazen RJ, Chan JH, Stuart DI, Stammers DK (2004) J Med Chem 47(24):5912

    Article  CAS  Google Scholar 

  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):268

    Article  CAS  Google Scholar 

  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. Monecke T, Güttler T, Neumann P, Dickmanns A, Görlich D, Ficner R (2009) Science 324(5930):1087

    Article  CAS  Google Scholar 

  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):1634

    Article  CAS  Google Scholar 

  51. Halgren T (2007) Chem Biol Drug Des 69(2):146

    Article  CAS  Google Scholar 

  52. Halgren T (2009) J Chem Inf Model 49:377

    Article  CAS  Google Scholar 

  53. Maestro v9.2. (2011) Schrödinger, Inc., Portland

  54. LigPrep v2.4. (2010) Schrödinger Inc., Portland

  55. Rogers D, Hahn M (2010) J Chem Inf Model 50(5):742

    Article  CAS  Google Scholar 

  56. Butina D (1999) J Chem Inf Comput Sci 39(4):747

    Article  CAS  Google Scholar 

  57. Prime v3.0. (2011) Schrödinger Inc., Portland

  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. Truchon J-F, Bayly CI (2007) J Chem Inf Model 47(2):488

    Article  CAS  Google Scholar 

  60. Salam NK, Nuti R, Sherman W (2009) J Chem Inf Model 49(10):2356

    Article  CAS  Google Scholar 

  61. Wang R, Lai L, Wang S (2002) J Comput Aided Mol Des 16(1):11

    Article  CAS  Google Scholar 

  62. Sastry M, Dixon S, Sherman W (2011) J Chem Inf Model 51(10):2455

    Article  CAS  Google Scholar 

  63. QikProp v2.0. (2011) Schrödinger Inc., Portland

  64. Daylight Chemical Information Systems (2008) Aliso Viejo

  65. Portevin B, Tordjman C, Pastoureau P, Bonnet J, De Nanteuil G (2000) J Med Chem 43(24):4582

    Article  CAS  Google Scholar 

  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):3515

    Article  CAS  Google Scholar 

  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):253

    Article  CAS  Google Scholar 

  68. Motakis D, Parniak MA (2002) Antimicrob Agents Chemother 46(6):1851

    Article  CAS  Google Scholar 

  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):2860

    Article  CAS  Google Scholar 

  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):2229

    Article  CAS  Google Scholar 

  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):7582

    Article  CAS  Google Scholar 

  72. Sun J, Meyers MJ, Fink BE, Rajendran R, Katzenellenbogen JA, Katzenellenbogen BS (1999) Endocrinology 140(2):800

    Article  CAS  Google Scholar 

  73. Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras D (2001) J Biol Chem 276(18):15059

    Article  CAS  Google Scholar 

  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):107

    Article  CAS  Google Scholar 

  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):2322

    Article  CAS  Google Scholar 

  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):3544

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Karyopharm Therapeutics, 2 Mercer Road, Natick, MA, 01760, USA

    Ori Kalid, Sharon Shechter & Sharon Shacham

  2. Ori Kalid Consulting, Habotnim 40, 37013, Pardes-Hanna, Israel

    Ori Kalid

  3. Schrödinger Inc., 120 West 45th Street, New York, NY, 10036, USA

    Dora Toledo Warshaviak & Woody Sherman

Authors
  1. Ori Kalid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dora Toledo Warshaviak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sharon Shechter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Woody Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sharon Shacham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ori Kalid.

Additional information

Ori Kalid, Dora Toledo Warshaviak: equal contributors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13399 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalid, O., Toledo Warshaviak, D., Shechter, S. et al. Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors. J Comput Aided Mol Des 26, 1217–1228 (2012). https://doi.org/10.1007/s10822-012-9611-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-012-9611-9

Keywords

Search

Navigation