Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content
Springer Nature Link
Log in

Avalanche for shape and feature-based virtual screening with 3D alignment

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

Abstract

This report introduces a new ligand-based virtual screening tool called Avalanche that incorporates both shape- and feature-based comparison with three-dimensional (3D) alignment between the query molecule and test compounds residing in a chemical database. Avalanche proceeds in two steps. The first step is an extremely rapid shape/feature based comparison which is used to narrow the focus from potentially millions or billions of candidate molecules and conformations to a more manageable number that are then passed to the second step. The second step is a detailed yet still rapid 3D alignment of the remaining candidate conformations to the query conformation. Using the 3D alignment, these remaining candidate conformations are scored, re-ranked and presented to the user as the top hits for further visualization and evaluation. To provide further insight into the method, the results from two prospective virtual screens are presented which show the ability of Avalanche to identify hits from chemical databases that would likely be missed by common substructure-based or fingerprint-based search methods. The Avalanche method is extended to enable patent landscaping, i.e., structural refinements to improve the patentability of hits for deployment in drug discovery campaigns.

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

Similar content being viewed by others

References

  1. Meek PJ, Liu Z, Tian L, Wang CY, Welsh WJ, Zauhar RJ (2006) Drug Discov Today 11(19–20):895

    Article  CAS  Google Scholar 

  2. Nagarajan K, Zauhar R, Welsh WJ (2005) J Chem Inf Model 45(1):49

    Article  CAS  Google Scholar 

  3. Zauhar RJ, Gianti E, Welsh WJ (2013) J Comput Aided Mol Des 27(12):1009

    Article  CAS  Google Scholar 

  4. Zauhar RJ, Moyna G, Tian L, Li Z, Welsh WJ (2003) J Med Chem 46(26):5674

    Article  CAS  Google Scholar 

  5. Hartman I, Gillies AR, Arora S, Andaya C, Royapet N, Welsh WJ, Wood DW, Zauhar RJ (2009) Pharm Res 26(10):2247

    Article  CAS  Google Scholar 

  6. Kortagere S, Chekmarev D, Welsh WJ, Ekins S (2008) Pharm Res 25(8):1836

    Article  CAS  Google Scholar 

  7. Kortagere S, Chekmarev D, Welsh WJ, Ekins S (2009) Pharm Res 26(4):1001

    Article  CAS  Google Scholar 

  8. Kortagere S, Mui E, McLeod R, Welsh WJ (2011) J Comput Aided Mol Des 25(5):403

    Article  CAS  Google Scholar 

  9. Kortagere S, Welsh WJ (2006) J Comput Aided Mol Des 20(12):789

    Article  CAS  Google Scholar 

  10. Kortagere S, Welsh WJ, Morrisey JM, Daly T, Ejigiri I, Sinnis P, Vaidya AB, Bergman LW (2010) J Chem Inf Model 50(5):840

    Article  CAS  Google Scholar 

  11. Chekmarev D, Kholodovych V, Kortagere S, Welsh WJ, Ekins S (2009) Pharm Res 26(9):2216

    Article  CAS  Google Scholar 

  12. Chekmarev DS, Kholodovych V, Balakin KV, Ivanenkov Y, Ekins S, Welsh WJ (2008) Chem Res Toxicol 21(6):1304

    Article  CAS  Google Scholar 

  13. Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, Young D, Welsh WJ (2006) Chem Res Toxicol 19(12):1595

    Article  CAS  Google Scholar 

  14. Ai N, Welsh WJ, Santhanam U, Hu H, Lyga J (2014) PLoS ONE 9(11):e112788

    Article  Google Scholar 

  15. Rush TS 3rd, Grant JA, Mosyak L, Nicholls A (2005) J Med Chem 48(5):1489

    Article  CAS  Google Scholar 

  16. Giganti D, Guillemain H, Spadoni JL, Nilges M, Zagury JF, Montes M (2010) J Chem Inf Model 50(6):992

    Article  CAS  Google Scholar 

  17. Sastry GM, Dixon SL, Sherman W (2011) J Chem Inf Model 51(10):2455

    Article  CAS  Google Scholar 

  18. Wolber G, Seidel T, Bendix F, Langer T (2008) Drug Discov Today 13(1–2):23

    Article  CAS  Google Scholar 

  19. Clinical and Laboratory Standards Institute (2012) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: 8th edn, M07-A9. CLSI, Wayne

    Google Scholar 

  20. Landrum G (2014) RDKit: Cheminformatics and machine learning software. http://www.rdkit.org/. Accessed 7 Aug 2014

  21. Ebejer JP, Morris GM, Deane CM (2012) J Chem Inf Model 52(5):1146

    Article  CAS  Google Scholar 

  22. Charifson PS, Grillot AL, Grossman TH, Parsons JD, Badia M, Bellon S, Deininger DD, Drumm JE, Gross CH, LeTiran A, Liao Y, Mani N, Nicolau DP, Perola E, Ronkin S, Shannon D, Swenson LL, Tang Q, Tessier PR, Tian SK, Trudeau M, Wang T, Wei Y, Zhang H, Stamos D (2008) J Med Chem 51(17):5243

    Article  CAS  Google Scholar 

  23. Noel DR, Casely RE, Linfield WM, Harriman LA (1960) Appl Microbiol 8:1

    CAS  Google Scholar 

  24. Fomovska A, Wood RD, Mui E, Dubey JP, Ferreira LR, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Welsh WJ, Sommerville C, Woods S, Roberts C, McLeod R (2012) J Med Chem 55(19):8375

    Article  CAS  Google Scholar 

  25. Kratky M, Vinsova J, Novotna E, Mandikova J, Wsol V, Trejtnar F, Ulmann V, Stolarikova J, Fernandes S, Bhat S, Liu JO (2012) Tuberculosis (Edinb) 92(5):434

    Article  CAS  Google Scholar 

  26. Vinsova J, Imramovsky A, Buchta V, Ceckova M, Dolezal M, Staud F, Jampilek J, Kaustova J (2007) Molecules 12(1):1

    Article  CAS  Google Scholar 

  27. Waisser K, Bures O, Holy P, Kunes J, Oswald R, Jiraskova L, Pour M, Klimesova V, Kubicova L, Kaustova J (2003) Arch Pharm (Weinheim) 336(1):53

    Article  CAS  Google Scholar 

  28. Waisser K, Matyk J, Divisova H, Husakova P, Kunes J, Klimesova V, Kaustova J, Mollmann U, Dahse HM, Miko M (2006) Arch Pharm (Weinheim) 339(11):616

    Article  CAS  Google Scholar 

  29. Gordon MS, Schmidt MW (2005) Advances in electronic structure theory: GAMESS a decade later. In: Dykstra CE, Frenking G, Kim KS, Scuseria GE (eds) Theory and applications of computational chemistry: the first forty years. Elsevier, Amsterdam (1167)

    Google Scholar 

  30. Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su S, Windus TL, Dupuis M, Montgomery JA (1993) J Comput Chem 14(11):1347

    Article  CAS  Google Scholar 

  31. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J (2009) Clin Infect Dis 48(1):1

    Article  Google Scholar 

  32. Gwynn MN, Portnoy A, Rittenhouse SF, Payne DJ (2010) Ann N Y Acad Sci 1213:5

    Article  Google Scholar 

  33. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Nat Rev Drug Discov 6(1):29

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. David J. Diller

    Present address: CMD Bioscience, 5 Science Park, New Haven, CT, 06511, USA

Authors and Affiliations

  1. Snowdon, Inc., Princeton, NJ, 08540, USA

    David J. Diller

  2. Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, 07103, USA

    Nancy D. Connell

  3. Department of Pharmacology, Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ, 08854, USA

    William J. Welsh

Authors
  1. David J. Diller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy D. Connell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William J. Welsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to David J. Diller or William J. Welsh.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diller, D.J., Connell, N.D. & Welsh, W.J. Avalanche for shape and feature-based virtual screening with 3D alignment. J Comput Aided Mol Des 29, 1015–1024 (2015). https://doi.org/10.1007/s10822-015-9875-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-015-9875-y

Keywords

Search

Navigation