Skip to main content
SpringerLink
Log in

Discovery of small molecules binding to the normal conformation of prion by combining virtual screening and multiple biological activity evaluation methods

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

Abstract

Conformational conversion of the normal cellular prion protein, PrPC, into the misfolded isoform, PrPSc, is considered to be a central event in the development of fatal neurodegenerative diseases. Stabilization of prion protein at the normal cellular form (PrPC) with small molecules is a rational and efficient strategy for treatment of prion related diseases. However, few compounds have been identified as potent prion inhibitors by binding to the normal conformation of prion. In this work, to rational screening of inhibitors capable of stabilizing cellular form of prion protein, multiple approaches combining docking-based virtual screening, steady-state fluorescence quenching, surface plasmon resonance and thioflavin T fluorescence assay were used to discover new compounds interrupting PrPC to PrPSc conversion. Compound 3253-0207 that can bind to PrPC with micromolar affinity and inhibit prion fibrillation was identified from small molecule databases. Molecular dynamics simulation indicated that compound 3253-0207 can bind to the hotspot residues in the binding pocket composed by β1, β2 and α2, which are significant structure moieties in conversion from PrPC to PrPSc.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF (1996) Nature 383:685–690

    Article  CAS  Google Scholar 

  2. Heinemann U, Krasnianski A, Meissner B, Varges D, Kallenberg K, Schulz-Schaeffer W, Steinhoff B, Grasbon-Frodl E, Kretzschmar H, Zerr I (2007) Brain 130(5):1350–1359

    Article  CAS  Google Scholar 

  3. Prusiner SB (1998) Proc Natl Acad Sci USA 95(23):13363–13383

    Article  CAS  Google Scholar 

  4. Collinge J (2001) Annu Rev Neurosci 24(1):519–550

    Article  CAS  Google Scholar 

  5. Stahl N, Baldwin MA, Teplow DB, Hood L, Gibson BW, Burlingame AL, Prusiner SB (1993) Biochemistry 32(8):1991–2002

    Article  CAS  Google Scholar 

  6. Sigurdson CJ, Nilsson KPR, Hornemann S, Heikenwalder M, Manco G, Schwarz P, Ott D, Rülicke T, Liberski PP, Julius C (2009) Proc Natl Acad Sci USA 106(1):304–309

    Article  CAS  Google Scholar 

  7. Castilla J, Saá P, Hetz C, Soto C (2005) Cell 121(2):195–206

    Article  CAS  Google Scholar 

  8. Pan K-M, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE (1993) Proc Natl Acad Sci USA 90(23):1096210966

    Article  Google Scholar 

  9. Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, Caughey WS (1991) Biochemistry 30(31):7672–7680

    Article  CAS  Google Scholar 

  10. Prusiner SB (1991) Science 252(5012):1515–1522

    Article  CAS  Google Scholar 

  11. Trevitt CR, Collinge J (2006) Brain 129(Pt 9):2241–2265

    Article  Google Scholar 

  12. Poncet-Montange G, St Martin SJ, Bogatova OV, Prusiner SB, Shoichet BK, Ghaemmaghami S (2011) J Biol Chem 286(31):27718–27728

    Article  CAS  Google Scholar 

  13. Ghaemmaghami S, May BC, Renslo AR, Prusiner SB (2010) J Virol 84(7):3408–3412

    Article  CAS  Google Scholar 

  14. Bertsch U, Winklhofer KF, Hirschberger T, Bieschke J, Weber P, Hartl FU, Tavan P, Tatzelt J, Kretzschmar HA, Giese A (2005) J Virol 79(12):7785–7791

    Article  CAS  Google Scholar 

  15. Giese A, Kretzschmar H (2001) Prion-induced neuronal damage—the mechanisms of neuronal destruction in the subacute spongiform encephalopathies. The mechanisms of neuronal damage in virus infections of the nervous system. Springer, Berlin, pp 203–217

    Book  Google Scholar 

  16. Antonyuk SV, Trevitt CR, Strange RW, Jackson GS, Sangar D, Batchelor M, Cooper S, Fraser C, Jones S, Georgiou T, Khalili-Shirazi A, Clarke AR, Hasnain SS, Collinge J (2009) Proc Natl Acad Sci USA 106(8):25542558

    Article  Google Scholar 

  17. Singh J, Udgaonkar JB (2015) Angew Chem Int Ed Engl 54(26):7529–7533

    Article  CAS  Google Scholar 

  18. Ghaemmaghami S, Russo M, Renslo AR (2014) J Med Chem 57(16):6919–6929

    Article  CAS  Google Scholar 

  19. Baral PK, Swayampakula M, Rout MK, Kav NN, Spyracopoulos L, Aguzzi A, James MN (2014) Structure 22(2):291–303

    Article  CAS  Google Scholar 

  20. Singh J, Kumar H, Sabareesan AT, Udgaonkar JB (2014) J Am Chem Soc 136(48):16704–16707

    Article  CAS  Google Scholar 

  21. Rester U (2008) Curr Opin Drug Discov Dev 11(4):559–568

    CAS  Google Scholar 

  22. Walters WP, Stahl MT, Murcko MA (1998) Drug Discov Today 3(4):160–178

    Article  CAS  Google Scholar 

  23. Lakowicz JR (1983) Quenching of fluorescence. Principles of fluorescence spectroscopy. Springer, New York, pp 277–330

    Book  Google Scholar 

  24. Mátyus L, Szöllősi J, Jenei A (2006) J Photochem Photobiol B 83(3):223–236

    Article  Google Scholar 

  25. Rich RL, Myszka DG (2003) J Mol Recognit 16(6):351–382

    Article  CAS  Google Scholar 

  26. Rich RL, Hoth LR, Geoghegan KF, Brown TA, LeMotte PK, Simons SP, Hensley P, Myszka DG (2002) Proc Natl Acad Sci USA 99(13):8562–8567

    Article  CAS  Google Scholar 

  27. Navratilova I, Hopkins AL (2010) ACS Med Chem Lett 1(1):44–48

    Article  CAS  Google Scholar 

  28. Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang S-H, Yang X, Zhang M-Y, Zwick MB, Arthos J (2007) Nature 445(7129):732–737

    Article  CAS  Google Scholar 

  29. Biancalana M, Makabe K, Koide A, Koide S (2009) J Mol Biol 385(4):1052–1063

    Article  CAS  Google Scholar 

  30. Luchsinger JA, Tang M, Siddiqui M, Shea S, Mayeux R (2004) J Am Geriatr Soc 52(4):540–546

    Article  Google Scholar 

  31. Xue W, Pan D, Yang Y, Liu H, Yao X (2012) Antiviral Res 93(1):126–137

    Article  CAS  Google Scholar 

  32. Dodson GG, Lane DP, Verma CS (2008) EMBO Rep 9(2):144–150

    Article  CAS  Google Scholar 

  33. Dror RO, Dirks RM, Grossman JP, Xu H, Shaw DE (2012) Annu Rev Biophys 41:429–452

    Article  CAS  Google Scholar 

  34. Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) J Phys Chem B 105(28):6474–6487

    Article  CAS  Google Scholar 

  35. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Prpasky MP, Knoll EH, Sheelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) J Med Chem 47:1739–1749

    Article  CAS  Google Scholar 

  36. Cross JB, Thompson DC, Rai BK, Baber JC, Fan KY, Hu Y, Humblet C (2009) J Chem Inf Model 49(6):1455–1474

    Article  CAS  Google Scholar 

  37. Bjorndahl TC, Zhou GP, Liu X, Perez-Pineiro R, Semenchenko V, Saleem F, Acharya S, Bujold A, Sobsey CA, Wishart DS (2011) Biochemistry 50(7):1162–1173

    Article  CAS  Google Scholar 

  38. Yin S-M, Zheng Y, Tien P (2003) Protein Expr Purif 32(1):104–109

    Article  CAS  Google Scholar 

  39. Bradford MM (1976) Anal Biochem 72(1–2):248–254

    Article  CAS  Google Scholar 

  40. Lakowicz JR, Weber G (1973) Biochemistry 12(21):4161–4170

    Article  CAS  Google Scholar 

  41. Mehra J, Rechenberg H (2001) The historical development of quantum theory. Volume 1 part 1 the quantum theory of Planck, Einstein, Bohr and Sommerfeld 1900–1925: its foundation and the rise of its difficulties. Springer, New York, pp 1900–1925

    Google Scholar 

  42. Frostell-Karlsson Å, Remaeus A, Roos H, Andersson K, Borg P, Hämäläinen M, Karlsson R (2000) J Med Chem 43(10):1986–1992

    Article  CAS  Google Scholar 

  43. Feltis B, Sexton B, Glenn F, Best M, Wilkins M, Davis T (2008) Biosens Bioelectron 23(7):1131–1136

    Article  CAS  Google Scholar 

  44. Bocharova OV, Breydo L, Parfenov AS, Salnikov VV, Baskakov IV (2005) J Mol Biol 346(2):645–659

    Article  CAS  Google Scholar 

  45. Baskakov IV (2004) J Biol Chem 279(9):7671–7677

    Article  CAS  Google Scholar 

  46. Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) J Comput Chem 26(16):1668–1688

    Article  CAS  Google Scholar 

  47. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JJA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09. Gaussian, Inc., Wallingford

    Google Scholar 

  48. Fox T, Kollman PA (1998) J Phys Chem B 102(41):8070–8079

    Article  CAS  Google Scholar 

  49. Bayly CI, Cieplak P, Cornell W, Kollman PA (1993) J Phys Chem 97(40):10269–10280

    Article  CAS  Google Scholar 

  50. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25(9):1157–1174

    Article  CAS  Google Scholar 

  51. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Proteins 78(8):1950–1958

    CAS  Google Scholar 

  52. Onufriev A, Bashford D, Case DA (2000) J Phys Chem B 104(15):3712–3720

    Article  CAS  Google Scholar 

  53. Tsui V, Case DA (2000) Biopolymers 56(4):275–291

    Article  CAS  Google Scholar 

  54. Massova I, Kollman PA (2000) Perspect Drug Discov 18(1):113–135

    Article  CAS  Google Scholar 

  55. Sitkoff D, Sharp KA, Honig B (1994) J Phys Chem 98(7):1978–1988

    Article  CAS  Google Scholar 

  56. Pearlman DA, Case DA, Caldwell JW, Ross WS, Cheatham TE, DeBolt S, Ferguson D, Seibel G, Kollman P (1995) Comput Phys Commun 91(1):1–41

    Article  CAS  Google Scholar 

  57. Baell JB, Holloway GA (2010) J Med Chem 53(7):2719–2740

    Article  CAS  Google Scholar 

  58. Rolinski OJ, Amaro M, Birch DJ (2010) Biosens Bioelectron 25(10):2249–2252

    Article  CAS  Google Scholar 

  59. Zhou Z, Yan X, Pan K, Chen J, Xie ZS, Xiao GF, Yang FQ, Liang Y (2011) Biophys J 101(6):1483–1492

    Article  CAS  Google Scholar 

  60. Zhou Z, Fan JB, Zhu HL, Shewmaker F, Yan X, Chen X, Chen J, Xiao GF, Guo L, Liang Y (2009) J Biol Chem 284(44):30148–30158

    Article  CAS  Google Scholar 

  61. Caughey B, Raymond GJ (1993) J Virol 67(2):643–650

    CAS  Google Scholar 

  62. Raymond GJ, Olsen EA, Lee KS, Raymond LD, Bryant PK, Baron GS, Caughey WS, Kocisko DA, McHolland LE, Favara C, Langeveld J, Zijiderveld F, Mayer RT, Miller MW, Williams ES, Caughery B (2006) J Virol 80(2):596–604

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Nature Science Foundation of China (Grant No. 21675070) and the Fundamental Research Funds for the Central Universities (Grant No. lzujbky-2016-146).

Author information

Authors and Affiliations

  1. State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Lanlan Li, Yan Zhang & Xiaojun Yao

  2. School of Pharmacy, Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Wei Wei, Yongchang Zhu, Yan Zhang, Jiaqi Tian & Huanxiang Liu

  3. School of Life Sciences, Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Wen-Juan Jia, Jiang-Huai Chen & Yong-Xing He

  4. State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, People’s Republic of China

    Xiaojun Yao

Authors
  1. Lanlan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-Juan Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yongchang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiang-Huai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiaqi Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huanxiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong-Xing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaojun Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huanxiang Liu, Yong-Xing He or Xiaojun Yao.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 2529 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Wei, W., Jia, WJ. et al. Discovery of small molecules binding to the normal conformation of prion by combining virtual screening and multiple biological activity evaluation methods. J Comput Aided Mol Des 31, 1053–1062 (2017). https://doi.org/10.1007/s10822-017-0086-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-017-0086-6

Keywords

Search

Navigation