Journal of Computer-Aided Molecular Design

, Volume 29, Issue 11, pp 1015–1024 | Cite as

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



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.


Virtual screening Shape matching Three dimensional alignment Antibacterial drug discovery 


  1. 1.
    Meek PJ, Liu Z, Tian L, Wang CY, Welsh WJ, Zauhar RJ (2006) Drug Discov Today 11(19–20):895CrossRefGoogle Scholar
  2. 2.
    Nagarajan K, Zauhar R, Welsh WJ (2005) J Chem Inf Model 45(1):49CrossRefGoogle Scholar
  3. 3.
    Zauhar RJ, Gianti E, Welsh WJ (2013) J Comput Aided Mol Des 27(12):1009CrossRefGoogle Scholar
  4. 4.
    Zauhar RJ, Moyna G, Tian L, Li Z, Welsh WJ (2003) J Med Chem 46(26):5674CrossRefGoogle Scholar
  5. 5.
    Hartman I, Gillies AR, Arora S, Andaya C, Royapet N, Welsh WJ, Wood DW, Zauhar RJ (2009) Pharm Res 26(10):2247CrossRefGoogle Scholar
  6. 6.
    Kortagere S, Chekmarev D, Welsh WJ, Ekins S (2008) Pharm Res 25(8):1836CrossRefGoogle Scholar
  7. 7.
    Kortagere S, Chekmarev D, Welsh WJ, Ekins S (2009) Pharm Res 26(4):1001CrossRefGoogle Scholar
  8. 8.
    Kortagere S, Mui E, McLeod R, Welsh WJ (2011) J Comput Aided Mol Des 25(5):403CrossRefGoogle Scholar
  9. 9.
    Kortagere S, Welsh WJ (2006) J Comput Aided Mol Des 20(12):789CrossRefGoogle Scholar
  10. 10.
    Kortagere S, Welsh WJ, Morrisey JM, Daly T, Ejigiri I, Sinnis P, Vaidya AB, Bergman LW (2010) J Chem Inf Model 50(5):840CrossRefGoogle Scholar
  11. 11.
    Chekmarev D, Kholodovych V, Kortagere S, Welsh WJ, Ekins S (2009) Pharm Res 26(9):2216CrossRefGoogle Scholar
  12. 12.
    Chekmarev DS, Kholodovych V, Balakin KV, Ivanenkov Y, Ekins S, Welsh WJ (2008) Chem Res Toxicol 21(6):1304CrossRefGoogle Scholar
  13. 13.
    Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, Young D, Welsh WJ (2006) Chem Res Toxicol 19(12):1595CrossRefGoogle Scholar
  14. 14.
    Ai N, Welsh WJ, Santhanam U, Hu H, Lyga J (2014) PLoS ONE 9(11):e112788CrossRefGoogle Scholar
  15. 15.
    Rush TS 3rd, Grant JA, Mosyak L, Nicholls A (2005) J Med Chem 48(5):1489CrossRefGoogle Scholar
  16. 16.
    Giganti D, Guillemain H, Spadoni JL, Nilges M, Zagury JF, Montes M (2010) J Chem Inf Model 50(6):992CrossRefGoogle Scholar
  17. 17.
    Sastry GM, Dixon SL, Sherman W (2011) J Chem Inf Model 51(10):2455CrossRefGoogle Scholar
  18. 18.
    Wolber G, Seidel T, Bendix F, Langer T (2008) Drug Discov Today 13(1–2):23CrossRefGoogle Scholar
  19. 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, WayneGoogle Scholar
  20. 20.
    Landrum G (2014) RDKit: Cheminformatics and machine learning software. Accessed 7 Aug 2014
  21. 21.
    Ebejer JP, Morris GM, Deane CM (2012) J Chem Inf Model 52(5):1146CrossRefGoogle Scholar
  22. 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):5243CrossRefGoogle Scholar
  23. 23.
    Noel DR, Casely RE, Linfield WM, Harriman LA (1960) Appl Microbiol 8:1Google Scholar
  24. 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):8375CrossRefGoogle Scholar
  25. 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):434CrossRefGoogle Scholar
  26. 26.
    Vinsova J, Imramovsky A, Buchta V, Ceckova M, Dolezal M, Staud F, Jampilek J, Kaustova J (2007) Molecules 12(1):1CrossRefGoogle Scholar
  27. 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):53CrossRefGoogle Scholar
  28. 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):616CrossRefGoogle Scholar
  29. 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. 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):1347CrossRefGoogle Scholar
  31. 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):1CrossRefGoogle Scholar
  32. 32.
    Gwynn MN, Portnoy A, Rittenhouse SF, Payne DJ (2010) Ann N Y Acad Sci 1213:5CrossRefGoogle Scholar
  33. 33.
    Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Nat Rev Drug Discov 6(1):29CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Snowdon, Inc.PrincetonUSA
  2. 2.CMD BioscienceNew HavenUSA
  3. 3.Department of Medicine, New Jersey Medical SchoolRutgers UniversityNewarkUSA
  4. 4.Department of PharmacologyCancer Institute of New Jersey, Rutgers UniversityPiscatawayUSA

Personalised recommendations