Skip to main content

Advertisement

SpringerLink
Log in

Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson–Boltzmann surface area calculations

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

Abstract

The objectives of this study include the design of a series of novel fullerene-based inhibitors for HIV-1 protease (HIV-1 PR), by employing two strategies that can also be applied to the design of inhibitors for any other target. Additionally, the interactions which contribute to the observed exceptionally high binding free energies were analyzed. In particular, we investigated: (1) hydrogen bonding (H-bond) interactions between specific fullerene derivatives and the protease, (2) the regions of HIV-1 PR that play a significant role in binding, (3) protease changes upon binding and (4) various contributions to the binding free energy, in order to identify the most significant of them. This study has been performed by employing a docking technique, two 3D-QSAR models, molecular dynamics (MD) simulations and the molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) method. Our computed binding free energies are in satisfactory agreement with the experimental results. The suitability of specific fullerene derivatives as drug candidates was further enhanced, after ADMET (absorption, distribution, metabolism, excretion and toxicity) properties have been estimated to be promising. The outcomes of this study revealed important protein–ligand interaction patterns that may lead towards the development of novel, potent HIV-1 PR inhibitors.

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
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Source available at http://www.unaids.org/

  2. Hamacher K (2008) Gene 422:30

    Article  CAS  Google Scholar 

  3. Navia MA, Fitzgerald PMD, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP (1989) Nature 337:615

    Article  CAS  Google Scholar 

  4. Jewell NA, Chen R, Raices R, Mansky LM (2003) J Antimicrob Chemother 52:547

    Article  CAS  Google Scholar 

  5. Trylska J, Tozzini V, Chang CA, McCammon JA (2007) Bioph J 92(12):4179

    Article  CAS  Google Scholar 

  6. Hornak V, Okur A, Rizzo RC, Simmerling CJ (2006) Am Chem Soc 128:2812

    Article  CAS  Google Scholar 

  7. Wensing AMJ, van Maarseveen NM, Nijhuis M (2010) Antiviral Res 85:59

    Article  CAS  Google Scholar 

  8. Hansch C, Unger SH (1977) J Med Chem 16(11):1217

    Article  Google Scholar 

  9. Friedman HS, DeCamp DL, Sijbesma RP, Srdanov G, Wudl F, Kenyon G (1993) J Am Chem Soc 115:6506

    Article  CAS  Google Scholar 

  10. Toniolo C, Bianco A, Maggini M, Scorrano G, Prate M, Marastoni M, Tomatis R, Spisani S, Palu G, Blair ED (1994) J Med Chem 37:4558

    Article  CAS  Google Scholar 

  11. Jafvert CT, Kulkarni PP (2008) Environ Sci Technol 42:5945

    Article  CAS  Google Scholar 

  12. Marchesan S, Da Ros T, Spalluto G, Balzarini J, Prato M (2005) Bioorg Med Chem Lett 15:3615

    Article  CAS  Google Scholar 

  13. Zhang HW, Coats SJ, Bondada L, Amblard F, Detorio M, Asif G, Fromentin E, Solomon S, Obikhod A, Whitaker T, Sluis-Cremer N, Mellors JW, Schinazi RF (2010) Bioorg Med Chem Lett 20:60

    Article  Google Scholar 

  14. Lee VS, Nimmanpipug P, Aruksakunwong O, Promsri S, Sompornpisut P, Hannongbua S (2007) J Mol Graph Model 26:558

    Article  CAS  Google Scholar 

  15. Troshina OA, Troshin PA, Peregudov AS, Kozlovskiy VI, Balzarini J, Lyubovskaya RN (2007) Org Biomol Chem 5:2783

    Article  CAS  Google Scholar 

  16. Promsri S, Chuichaya P, Sanghiranb V, Parasuka V, Hannongbua S (2005) J Mol Struct THEOCHEM 715:47

    Article  CAS  Google Scholar 

  17. Durdagi S, Mavromoustakos T, Chronakis N, Papadopoulos MG (2008) Bioorg Med Chem 16:9957

    Article  CAS  Google Scholar 

  18. Durdagi S, Mavromoustakos T, Papadopoulos MG (2008) Bioorg Med Chem Lett 18:6283

    Article  CAS  Google Scholar 

  19. Durdagi S, Supuran CT, Strom A, Doostdar N, Kumar MK, Barron AR, Mavromoustakos T, Papadopoulos MG (2009) J Chem Inf Model 49:1139

    Article  CAS  Google Scholar 

  20. Waterbeemd H, Gifford E (2003) Nat Rev Drug Discov 2:192

    Article  Google Scholar 

  21. ArgusLab 4.0.1 Mark A. Thompson Planaria Software LLC, Seattle, WA www.arguslab.com

  22. Rappe AK, Casewit CJ, Colwell KS, Goddard WA III, Skiff WM (1992) J Am Chem Soc 114:10024

    Article  CAS  Google Scholar 

  23. Broyden CG (1970) 6:76–90; Fletcher R (1970) 13:317–322; Goldfarb DA (1970) 24:23–26; Shanno DF (1970) Math Comput 24:647

  24. Leach AR (2001) Molecular modelling: principles and applications. 2nd Edn. Pearson Education Ltd

  25. Sengupta D, Verma D, Naik PK (2007) J Biosci 32:1316

    Article  Google Scholar 

  26. SYBYL 8.0, Tripos International, 1699 South Hanley Rd., St. Louis, Missouri, 63144, USA

  27. Case DA, Cheatham T, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods R (2005) J Computat Chem 26:1668

    Article  CAS  Google Scholar 

  28. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Merz M, Wang B, Hayik S, Roitberg SA, Seabra I, Wong F, Paesani J, Vanicek X, Wu SR, Brozell V, Tsui H, Gohlke L, Yang C, Tan J, Mongan V, Hornak G, Cui P, Beroza DH, Mathews C, Schafmeister WS, Ross, Kollman PA (2006) AMBER 9, University of California, San Francisco

  29. RSCB Protein Databank; http://www.rcsb.org/pdb/home/home.do

  30. Hyland LJ, Tomaszek TA Jr, Roberts GD, Carr SA, Magaard VW, Bryan HL, Fakhoury SA, Moore ML, Minnich MD (1991) Biochemistry 30:8454

    Article  CAS  Google Scholar 

  31. Zhu Z, Schuster DI, Tuckerman ME (2003) Biochemistry 42:1326

    Article  CAS  Google Scholar 

  32. Pietrucci F, Marinelli F, Carloni P, Laio A (2009) J Am Chem Soc 131:11811

    Article  CAS  Google Scholar 

  33. Piana S, Sebastiani D, Carloni P, Parrinello M (2001) J Am Chem Soc 123:8730

    Article  CAS  Google Scholar 

  34. Hou T, McLaughlin WA, Wang W (2008) Proteins 71:1163

    Article  CAS  Google Scholar 

  35. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C (2006) Proteins 65:712

    Article  CAS  Google Scholar 

  36. Wang J, Wolf RM, Caldwell JW, Kollamn PA, Case DA (2004) J Comput Chem 25:1157

    Article  CAS  Google Scholar 

  37. Jakalian A, Bush BL, Jack DB, Bayly CI (2000) J Comput Chem 21:132

    Article  CAS  Google Scholar 

  38. Jakalian A, Jack DB, Bayly CI (2002) J Comput Chem 23:1623

    Article  CAS  Google Scholar 

  39. Jorgensen WLCJ, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926

    Article  CAS  Google Scholar 

  40. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089

    Article  CAS  Google Scholar 

  41. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) J Comput Phys 23:327

    Article  CAS  Google Scholar 

  42. Izaguirre JA, Catarello DP, Wozniak JM, Skeel RD (2001) J Chem Phys 114:2090

    Article  CAS  Google Scholar 

  43. Kollman PA et al (2000) Acc Chem Rev 33:889

    Article  CAS  Google Scholar 

  44. Sitkoff D, Sharp KA, Honig B (1998) J Phys Chem 98:1978

    Article  Google Scholar 

  45. Srinivasan J, Cheatham TE, Cieplak P, Kollman PA (1998) J Am Chem Soc 120:9401

    Article  CAS  Google Scholar 

  46. Wang W, Donini O, Reyes CM, Kollman PA (2001) Annu Rev Biophys Biomol Struct 30:211

    Article  CAS  Google Scholar 

  47. Gouda H, Kuntz ID, Case DA, Kollman PA (2003) Biopolymers 68:16

    Article  CAS  Google Scholar 

  48. Stoica I, Sadiq SK, Coveney PV (2008) J Am Chem Soc 130:2639

    Article  CAS  Google Scholar 

  49. Hou T, Wang J, Li Y, Wang W (2011) J Chem Inf Model 51:69

    Article  CAS  Google Scholar 

  50. QikProp, version 3.3, Schrödinger, LLC, New York, NY, 2009

  51. Yazdanian M, Glynn SL, Wright JL, Hawi A (1998) Pharm Res 15:1490

    Article  CAS  Google Scholar 

  52. Irvine JD, Takahashi L, Lockhart K, Cheong J, Tolan JW, Selick HE, Grove JR (1999) J Pharm Sci 88:28

    Article  CAS  Google Scholar 

  53. Durdagi S, Subbotina J, Lees-Miller J, Guo, J, Duff HJ, Noskov SY (2010) Curr Med Chem 17:3514

    Google Scholar 

  54. Ajay, Bemis GW, Murcko MA (1999) J Med Chem 42:4942

    Article  CAS  Google Scholar 

  55. Friedman HS, Ganapathi PS, Rubin PS, Kenyon GL (1998) J Med Chem 41:2424

    Article  CAS  Google Scholar 

  56. Bingel C (1993) Chem Ber 126:1957

    Article  CAS  Google Scholar 

  57. Ganapathi PS, Friedman SH, Kenyon GL, Rubin YJ (1995) Org Chem 60:2954

    Article  CAS  Google Scholar 

  58. Freedberg DJ, Ishima R, Jacob J, Wang YX, Kustanovich I, Louis JM, Trochia DA (2002) Protein Sci 11:221

    Article  CAS  Google Scholar 

  59. Zoete V, Michielin O, Karplus M (2002) J Mol Biol 315:21

    Article  CAS  Google Scholar 

  60. Reyes CM, Kollman PA (2000) J Mol Biol 297:1145

    Article  CAS  Google Scholar 

  61. Wang CW, Lim WA, Jakalian A, Wang J, Wang M, Luo R, Bayly CT, Kollman PA (2001) J Am Chem Soc 123:3986

    Article  CAS  Google Scholar 

  62. Hou T, Yu R (2008) J Med Chem 50:1177

    Article  Google Scholar 

  63. Cai Y, Schiffer CA (2010) J Chem Theory Comp 6:1358

    Article  CAS  Google Scholar 

  64. Charlier L, Nespoulous C, Fiorucci S, Antonczak S, Golebiowski G (2007) Phys Chem Chem Phys 9:576

    Article  Google Scholar 

  65. http://www.gene.com/gene/products/information/invirase/

  66. Ioakimidis L, Thoukydidis L, Mirza A, Naeem S, Reynisson J (2008) QSAR Comb Sci 4:445

    Article  Google Scholar 

  67. Luo S, Wang Z, Patel M, Khurana V, Zhu X, Pal D, Mitra AK (2011) Int J Pharm 414:77

    Article  CAS  Google Scholar 

  68. Anson BD, Weaver JGR, Ackerman MJ, Akinsete O, Henry K, January CT, Badley AD (2005) Lancet 365:682

    CAS  Google Scholar 

  69. Ohtaka H, Velazquez-Campoy A, Xie D, Freire E (2002) Protein Sci 11:1908

    Article  CAS  Google Scholar 

  70. Chen Z, Li Y, Cheng E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC (1994) J Biol Chem 269:26344

    CAS  Google Scholar 

  71. Kaldor SW, Kailsah VJ, Davies JF II, Shetty BV, Fritz JE, Appelt K, Burgess JA, Campanale KM, Chirgadze NY, Clawson DK, Dressman BA, Hatch SD, Khalil DA, Kosa MB, Lubbehusen PP, Muesing MA, Patick AK, Reich SH, Su KS, Tatlock JH (1997) J Med Chem 40:3797

    Article  Google Scholar 

  72. Mongan J, Case DA, McCammon JA (2004) J Comput Chem 25:2038

    Article  CAS  Google Scholar 

  73. Lefebvre E, Schiffer CA (2008) AIDS Rev 10:131–142

    Google Scholar 

  74. Muzammil S, Armstrong AA, Kang LW, Jakalian A, Bonneau PR, Schmelmer V, Amzel LM, Freire E (2007) J Virol 81:5144

    Article  CAS  Google Scholar 

  75. Ioannou E, Hirsch A, Elemes Y (2007) Tetrahedron 63:7070

    Article  CAS  Google Scholar 

  76. Giordani S, Colomer JF, Cattaruzza F, Alfonsi J, Meneghetti M, Prato M, Bonifazi D, Carbon, (2009) 47:578

  77. Tasis D, Tagmatarchis N, Georgakilas V, Gamboz C, Soranzo MR, Prato M (2003) C. R. Chimie (2003) 6:597

    Google Scholar 

  78. Bjelakovic MS, Godjevac DM, Milic DR (2007) Carbon 45:2260

    Article  CAS  Google Scholar 

  79. Tsumoto H, Takahashi K, Suzuki T, Nakagawa H, Kohda K, Miyata N (2008) Bioorg Med Chem Lett 18:657

    Article  CAS  Google Scholar 

  80. Huang ST, Ho CS, Lin CM, Fang HW, Peng YX (2008) Bioorg Med Chem 16:8619

    Article  CAS  Google Scholar 

  81. de Freitas RP, Iehl J, Delavaux-Nicot B, Nierengarten JF (2008) Tetrahedron 64:11409

    Google Scholar 

  82. Thompson BC, Frechet JM (2008) Angew Chem Int Ed 47:58

    Article  CAS  Google Scholar 

  83. Loboda O, Zalesny R, Avramopoulos A, Luis JM, Kirtman B, Tagmatarchis N, Reis H, Papadopoulos MG (2009) J Phys Chem A 113(6):1159

    Article  CAS  Google Scholar 

  84. Zalesny R, Loboda O, Iliopoulos K, Chatzikyriakos G, Couris S, Rotas G, Tagmatarchis N, Avramopoulos A, Papadopoulos MG (2010) Phys Chem Chem Phys 12:373

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge the CINECA award under the ISCRA initiative, for the availability of high performance computing resources and support. This work was supported by funding provided by the European Commission for the FP7-REGPOT-2009-1 Project ‘ARCADE’ (Grant Agreement No. 245866). Also, the research has been co-financed by the European Union (European Social Fund–ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)–Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund.

Author information

Authors and Affiliations

  1. Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Ave, 11635, Athens, Greece

    Haralambos Tzoupis, Georgios Leonis, Thomas Mavromoustakos & Manthos G. Papadopoulos

  2. Chemistry Department, National and Kapodistrian University of Athens, Panepistimioupolis Zographou, 15771, Athens, Greece

    Haralambos Tzoupis, Varnavas Mouchlis & Thomas Mavromoustakos

  3. Department of Biological Sciences, Institute of Biocomplexity and Informatics, University of Calgary, 2500 University Drive, Calgary, AB, T2N 1N4, Canada

    Serdar Durdagi

Authors
  1. Haralambos Tzoupis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georgios Leonis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Serdar Durdagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Varnavas Mouchlis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Mavromoustakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manthos G. Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Georgios Leonis or Manthos G. Papadopoulos.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 768 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tzoupis, H., Leonis, G., Durdagi, S. et al. Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson–Boltzmann surface area calculations. J Comput Aided Mol Des 25, 959–976 (2011). https://doi.org/10.1007/s10822-011-9475-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-011-9475-4

Keywords

Search

Navigation