Journal of Computer-Aided Molecular Design

, Volume 29, Issue 8, pp 757–776 | Cite as

Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches

  • Rino Ragno
  • Flavio Ballante
  • Adele Pirolli
  • Richard B. WickershamIII
  • Alexandros Patsilinakos
  • Stéphanie Hesse
  • Enrico Perspicace
  • Gilbert Kirsch
Article

Abstract

Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure–activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models’ predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors.

Keywords

Vascular endothelial growth factor receptor-2 (VEGFR-2) Structure-based drug design (SBDD) Ligand-based drug design (LBDD) 3-D QSAR Molecular docking 3-D QSAutogrid/R 

Supplementary material

10822_2015_9859_MOESM1_ESM.doc (1.4 mb)
Supplementary material 1 (DOC 1443 kb)

References

  1. 1.
    Ribatti D, Vacca A, Nico B, Roncali L, Dammacco F (2001) Mech Dev 100(2):157CrossRefGoogle Scholar
  2. 2.
    Risau W (1997) Nature 386(6626):671CrossRefGoogle Scholar
  3. 3.
    Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Pharmacol Rev 56(4):549CrossRefGoogle Scholar
  4. 4.
    Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N, Ferrara N (2001) J Biol Chem 276(5):3222CrossRefGoogle Scholar
  5. 5.
    Arora A, Scholar EM (2005) J Pharmacol Exp Ther 315(3):971CrossRefGoogle Scholar
  6. 6.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) Nat Rev Mol Cell Biol 7(5):359CrossRefGoogle Scholar
  7. 7.
    Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) J Clin Invest 106(4):511CrossRefGoogle Scholar
  8. 8.
    Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, Hlatky L, Vajkoczy P, Huber PE, Folkman J, Abdollahi A (2009) Cancer Res 69(3):836CrossRefGoogle Scholar
  9. 9.
    Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J (1972) J Exp Med 136(2):261CrossRefGoogle Scholar
  10. 10.
    Posey JA, Ng TC, Yang B, Khazaeli MB, Carpenter MD, Fox F, Needle M, Waksal H, LoBuglio AF (2003) Clin Cancer Res 9(4):1323Google Scholar
  11. 11.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Nat Rev Drug Discov 3(5):391CrossRefGoogle Scholar
  12. 12.
    Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH (2011) Mol Cancer Ther 10(12):2298CrossRefGoogle Scholar
  13. 13.
    Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, Srinivasan R (2013) J Clin Oncol 31(2):181CrossRefGoogle Scholar
  14. 14.
    Garofalo A, Goossens L, Six P, Lemoine A, Ravez S, Farce A, Depreux P (2011) Bioorg Med Chem Lett 21(7):2106CrossRefGoogle Scholar
  15. 15.
    Hu E, Tasker A, White RD, Kunz RK, Human J, Chen N, Burli R, Hungate R, Novak P, Itano A, Zhang X, Yu V, Nguyen Y, Tudor Y, Plant M, Flynn S, Xu Y, Meagher KL, Whittington DA, Ng GY (2008) J Med Chem 51(11):3065CrossRefGoogle Scholar
  16. 16.
    La DS, Belzile J, Bready JV, Coxon A, DeMelfi T, Doerr N, Estrada J, Flynn JC, Flynn SR, Graceffa RF, Harriman SP, Larrow JF, Long AM, Martin MW, Morrison MJ, Patel VF, Roveto PM, Wang L, Weiss MM, Whittington DA, Teffera Y, Zhao Z, Polverino AJ, Harmange JC (2008) J Med Chem 51(6):1695CrossRefGoogle Scholar
  17. 17.
    Miyazaki Y, Matsunaga S, Tang J, Maeda Y, Nakano M, Philippe RJ, Shibahara M, Liu W, Sato H, Wang L, Nolte RT (2005) Bioorg Med Chem Lett 15(9):2203CrossRefGoogle Scholar
  18. 18.
    Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H (2007) J Med Chem 50(4):611CrossRefGoogle Scholar
  19. 19.
    Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter RN 3rd, Johnson JH, Knick VB, Laudeman CP, Luttrell DK, Mook RA, Nolte RT, Rudolph SK, Szewczyk JR, Truesdale AT, Veal JM, Wang L, Stafford JA (2008) J Med Chem 51(15):4632CrossRefGoogle Scholar
  20. 20.
    Perspicace E, Jouan-Hureaux V, Ragno R, Ballante F, Sartini S, La Motta C, Da Settimo F, Chen B, Kirsch G, Schneider S, Faivre B, Hesse S (2013) Eur J Med Chem 63:765CrossRefGoogle Scholar
  21. 21.
    Du J, Lei B, Qin J, Liu H, Yao X (2009) J Mol Graph Model 27(5):642CrossRefGoogle Scholar
  22. 22.
    Jiang Q, Liao H, Yang Q, Zan W, Zang Z (2010) Mol Simul 36(9):693CrossRefGoogle Scholar
  23. 23.
    Jiang X, Ou G, Yan D, Zhang M, Yuan X (2011) Lett Drug Des Discov 8(10):926CrossRefGoogle Scholar
  24. 24.
    Kansal N, Silakari O, Ravikumar M (2008) Lett Drug Des Discov 5(7):437CrossRefGoogle Scholar
  25. 25.
    Kar RK, Suryadevara P, Sahoo BR, Sahoo GC, Dikhit MR, Das P (2013) SAR QSAR Environ Res 24(3):215CrossRefGoogle Scholar
  26. 26.
    Kumar Teli M, Hanumanthappa P, Krishnamurthy RG (2012) Lett Drug Des Discov 9(10):899CrossRefGoogle Scholar
  27. 27.
    Lan P, Sun JR, Chen WN, Sun PH, Chen WM (2011) J Enzyme Inhib Med Chem 26(3):367CrossRefGoogle Scholar
  28. 28.
    Lu X, Chen Y, You Q (2009) QSAR Comb Sci 28(11–12):1524CrossRefGoogle Scholar
  29. 29.
    Munoz C, Adasme F, Alzate-Morales JH, Vergara-Jaque A, Kniess T, Caballero J (2012) J Mol Graph Model 32:39CrossRefGoogle Scholar
  30. 30.
    Neaz M, Pasha F, Muddassar M, Lee SH, Sim T, Hah J-M, Cho SJ (2009) Med Chem Res 18(2):127CrossRefGoogle Scholar
  31. 31.
    Pasha FA, Muddassar M, Neaz MM, Cho SJ (2009) J Mol Graph Model 28(1):54CrossRefGoogle Scholar
  32. 32.
    Rajagopalan M, Balasubramanian S, Ramaswamy A, Mathur PP (2013) J Enzyme Inhib Med Chem 28(6):1236CrossRefGoogle Scholar
  33. 33.
    Sharma BK, Sharma SK, Singh P, Sharma S (2008) J Enzyme Inhib Med Chem 23(2):168CrossRefGoogle Scholar
  34. 34.
    Ugale VG, Patel HM, Surana SJ  (2013) Arab J Chem 119Google Scholar
  35. 35.
    Wu X, Wu S, Chen WH (2012) J Mol Model 18(3):1207CrossRefGoogle Scholar
  36. 36.
    Zeng H, Zhang H (2010) J Mol Graph Model 29(1):54CrossRefGoogle Scholar
  37. 37.
    Zhang Y, Liu H, Jiao Y, Yuan H, Wang F, Lu S, Yao S, Ke Z, Tai W, Jiang Y, Chen Y, Lu T (2012) Mol Divers 16(4):787CrossRefGoogle Scholar
  38. 38.
    Ballante F, Ragno R (2012) J Chem Inf Model 52(6):1674CrossRefGoogle Scholar
  39. 39.
    Ballante F, Caroli A, Wickersham RB 3rd, Ragno R (2014) J Chem Inf Model 54(3):956CrossRefGoogle Scholar
  40. 40.
    Ballante F, Tempera G, Agostinelli E, Ragno R (2013) Amino Acids 45(3):563CrossRefGoogle Scholar
  41. 41.
    Friggeri L, Ballante F, Ragno R, Musmuca I, De Vita D, Manetti F, Biava M, Scipione L, Di Santo R, Costi R, Feroci M, Tortorella S (2013) J Chem Inf Model 53(6):1463CrossRefGoogle Scholar
  42. 42.
    Caroli A, Ballante F, Wickersham RB 3rd, Corelli F, Ragno R (2014) J Chem Inf Model 54(3):970CrossRefGoogle Scholar
  43. 43.
    Ragno R (2009) VEGFR-2 inhibitors. Ligand-based, structure-based and 3-D QSAR studies as tools to design new small molecules. XXIII Congresso Nazionale della Società Chimica Italiana. Sorrento, ItalyGoogle Scholar
  44. 44.
    Berman HM, Bhat TN, Bourne PE, Feng Z, Gilliland G, Weissig H, Westbrook J (2000) Nat Struct Biol 7 Suppl:957CrossRefGoogle Scholar
  45. 45.
    Musmuca I, Caroli A, Mai A, Kaushik-Basu N, Arora P, Ragno R (2010) J Chem Inf Model 50(4):662CrossRefGoogle Scholar
  46. 46.
    Ragno R, Frasca S, Manetti F, Brizzi A, Massa S (2005) J Med Chem 48(1):200CrossRefGoogle Scholar
  47. 47.
    Castellano S, Stefancich G, Ragno R, Schewe K, Santoriello M, Caroli A, Hartmann RW, Sbardella G (2008) Bioorg Med Chem 16(18):8349CrossRefGoogle Scholar
  48. 48.
    Jain AN (2004) J Med Chem 47(4):947CrossRefGoogle Scholar
  49. 49.
    OpenEye Scientific Software SF, NM. OMEGA 2.5.1.4Google Scholar
  50. 50.
    Hawkins PC, Skillman AG, Warren GL, Ellingson BA, Stahl MT (2010) J Chem Inf Model 50(4):572CrossRefGoogle Scholar
  51. 51.
    OpenEye Scientific Software SF, NM. ROCS. 3.2.0.4Google Scholar
  52. 52.
    Hawkins PC, Skillman AG, Nicholls A (2007) J Med Chem 50(1):74CrossRefGoogle Scholar
  53. 53.
    Vainio MJ, Johnson MS (2007) J Chem Inf Model 47(6):2462CrossRefGoogle Scholar
  54. 54.
    Puranen JS, Vainio MJ, Johnson MS (2010) J Comput Chem 31(8):1722Google Scholar
  55. 55.
    Vainio MJ, Puranen JS, Johnson MS (2009) J Chem Inf Model 49(2):492CrossRefGoogle Scholar
  56. 56.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) J Comput Chem 30(16):2785CrossRefGoogle Scholar
  57. 57.
    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comput Chem 25(13):1605CrossRefGoogle Scholar
  58. 58.
    Yuriev E, Ramsland PA (2013) J Mol Recognit 26(5):215CrossRefGoogle Scholar
  59. 59.
    O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) J Cheminform 3:33CrossRefGoogle Scholar
  60. 60.
    Wold S, Johansson E, Cocchi M (1993) PLS: partial least squares projections to latent structures in 3D QSAR in drug design: theory, methods and applications. ESCOM Science PublishersGoogle Scholar
  61. 61.
    Xia Y, Song X, Li D, Ye T, Xu Y, Lin H, Meng N, Li G, Deng S, Zhang S, Liu L, Zhu Y, Zeng J, Lei Q, Pan Y, Wei Y, Zhao Y, Yu L (2014) Sci Rep 4:6031Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Rino Ragno
    • 1
    • 2
  • Flavio Ballante
    • 1
    • 3
  • Adele Pirolli
    • 1
  • Richard B. WickershamIII
    • 3
  • Alexandros Patsilinakos
    • 1
    • 2
  • Stéphanie Hesse
    • 4
  • Enrico Perspicace
    • 4
    • 5
  • Gilbert Kirsch
    • 4
  1. 1.Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del FarmacoSapienza Università di RomaRomeItaly
  2. 2.Magma Dynamics srl, Dipartimento di Chimica e Tecnologie del FarmacoSapienza Università di RomaRomeItaly
  3. 3.Department of Biochemistry and Molecular BiophysicsWashington University in St. Louis School of MedicineSt. LouisUSA
  4. 4.SRSMC UMR CNRS7565 (former LIMBP)MetzFrance
  5. 5.Genfit, Parc EurasantéLossFrance

Personalised recommendations