Skip to main content
SpringerLink
Log in

Molecular dynamics simulation and density functional theory studies on the active pocket for the binding of paclitaxel to tubulin

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Paclitaxel (PTX) is used to treat various cancers, but it also causes serious side effects and resistance. To better design similar compounds with less toxicity and more activity against drug-resistant tumors, it is important to clearly understand the PTX-binding pocket formed by the key residues of active sites on β-tubulin. Using a docking method, molecular dynamics (MD) simulation and density functional theory (DFT), we identified some residues (such as Arg278, Asp26, Asp226, Glu22, Glu27, His229, Arg369, Lys218, Ser277 and Thr276) on β-tubulin that are the active sites responsible for interaction with PTX. Another two residues, Leu371 and Gly279, also likely serve as active sites. Most of these sites contact with the “southern hemisphere” of PTX; only one key residue interacts with the “northern hemisphere” of PTX. These key residues can be divided into four groups, which serve as active compositions in the formation of an active pocket for PTX binding to β-tubulin. This active binding pocket enables a very strong interaction (the strength is predicted to be in the range of −327.8 to −365.7 kJ mol−1) between β-tubulin and PTX, with various orientated conformations. This strong interaction means that PTX possesses a high level of activity against cancer cells, a result that is in good agreement with the clinical mechanism of PTX. The described PTX pocket and key active residues will be applied to probe the mechanism of tumor cells resistant to PTX, and to design novel analogs with superior properties.

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

Chart 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Brown DT (2003) Taxus: the genus Taxus. Taylor and Francis, London

  2. Eisenhauer EA, Vermorken JB (1998) Drugs 55:5–30

    Article  CAS  Google Scholar 

  3. Consumer Project on Technology (2010) Disputes involving Paclitaxel, a cancer drug sold under different brand names, including Taxol. http://www.cptech.org/ip/health/taxol/

  4. Giannakakou P, Snyder JP (2008) In: Fojo T (ed) Tubulin and microtubules. Humana, Totowa

  5. Goodman J, Walsh V (2001) The story of taxol: nature and politics in the pursuit of an anti-cancer drug. Cambridge University Press, Cambridge

  6. Kuppens IE (2006) Curr Clin Pharmacol 1:57–70

    Article  CAS  Google Scholar 

  7. Mooberry SL (2007) Methods Mol Med 137:289–302

    Article  CAS  Google Scholar 

  8. Schiff PB, Fant J, Horwitz SB (1979) Nature 277:665–667

    Article  CAS  Google Scholar 

  9. Scripture CD, Figg WD, Sparreboom A (2006) Curr Neuropharmacol 4:165–172

    Article  CAS  Google Scholar 

  10. Cowden CJ, Paterson I (1997) Nature 387:238–239

    Article  CAS  Google Scholar 

  11. Drukman S, Kavallaris M (2002) Int J Oncol 21:621–628

    CAS  Google Scholar 

  12. Dumontet C, Sikic BI (1999) J Clin Oncol 17:1061–1070

    CAS  Google Scholar 

  13. Alcaraz AA, Mehta AK, Johnson SA, Snyder JP (2006) J Med Chem 49:2478–2488

    Article  CAS  Google Scholar 

  14. Baker JK (1992) Spectrosc Lett 25:31–48

    Article  CAS  Google Scholar 

  15. Dubois J, Guénard D, Guéritte-Voegelein F, Guédira N, Potier P, Gillet B, Beloeil JC (1993) Tetrahedron 49:6533–6544

    Article  CAS  Google Scholar 

  16. Freedman H, Huzil JT, Luchko T, Luduen RF, Tuszynski JA (2009) J Chem Inf Model 49:424–436

    Article  CAS  Google Scholar 

  17. Geney R, Sun L, Pera P, Bernacki RJ, Xia S, Horwitz SB, Simmerling CL, Ojima I (2005) Chem Biol 12:339–348

    Article  CAS  Google Scholar 

  18. Hilton BD, Chmurny GN, Muschik GM (1992) J Nat Prod 55:1157–1161

    Article  CAS  Google Scholar 

  19. Hodge M, Chen QH, Bane S, Sharma S, Loew M, Banerjee A, Alcaraz AA, Snyder JP, Kingston DGI (2009) Bioorg Med Chem Lett 19:2884–2887

    Article  CAS  Google Scholar 

  20. Ivery TGM, Le T (2003) Oncol Res 14:1–19

    CAS  Google Scholar 

  21. Jiang Y, Alcaraz AA, Chen JM, Kobayashi H, Lu YJ, Snyder JP (2006) J Med Chem 49:1891–1899

    Article  CAS  Google Scholar 

  22. Jiang Y, Lin HX, Chen JM, Chen MQ (2005) Bioorg Med Chem Lett 15:839–842

    Article  CAS  Google Scholar 

  23. Johnson SA, Alcaraz A, Snyder JP (2005) Org Lett 7:5549–5552

    Article  CAS  Google Scholar 

  24. Nogales E, Whittaker M, Milligan RA, Downing KH (1999) Cell 96:79–88

    Article  CAS  Google Scholar 

  25. Nogales E, Wolf SG, Khan IA, Luduena RF, Downing KH (1995) Nature 375:424–427

    Article  CAS  Google Scholar 

  26. Ojima I, Inoue T, Chakravarty S (1999) J Fluorine Chem 97:3–10

    Article  CAS  Google Scholar 

  27. Ojima I, Chakravarty S, Inoue T, Lin S, He L, Horwitz SW, Kuduk SD, Danishefsky SJ (1999) Proc Natl Acad Sci USA 96:4256–4261

    Article  CAS  Google Scholar 

  28. Ojima I, Kuduk SD, Chakravarty S, Ourevitch M, Bégue J-P (1997) J Am Chem Soc 119:5519–5527

    Article  CAS  Google Scholar 

  29. Paloma LG, Guy RK, Wrasidlo W, Nicolaou KC (1994) Chem Biol 1:107–112

    Article  Google Scholar 

  30. Querolle O, Dubois J, Thoret S, Roussi F, Guéritte F, Guénard D (2004) J Med Chem 47:5937–5944

    Article  CAS  Google Scholar 

  31. Shanker N, Kingston DGI, Ganesh T, Yang C, Alcaraz AA, Geballe MT, Banerjee A, McGee D, Snyder JP, Bane S (2007) Biochemistry 46:11514–11527

    Article  CAS  Google Scholar 

  32. Snyder JP, Nevins N, Cicero DO, Jasen J (2000) J Am Chem Soc 122:724–725

    Article  CAS  Google Scholar 

  33. Velde DGV, Georg GI, Grunewald GL, Gunn CW, Mitscher LA (1993) J Am Chem Soc 113:11650–11651

    Article  Google Scholar 

  34. Williams HJ, Scott AI, Dieden RA, Swindell CS, Chirlian LE, Francl MM, Heerding JM, Krauss NE (1993) Tetrahedron 49:6545–6560

    Article  CAS  Google Scholar 

  35. Wu Q, Bounaud PY, Kuduk SD, Yang CP, Ojima I, Horwitz SB, Orr GA (1998) Biochemistry 37:11272–11279

    Article  CAS  Google Scholar 

  36. Wang H, Nogales E (2005) Nature 435:911–915

    Article  CAS  Google Scholar 

  37. Kingston DGI (2009) J Nat Prod 72:507–515

    Article  CAS  Google Scholar 

  38. Jordan M, Wendell K, Gardiner S, Derry W, Copp H, Wilson L (1996) Cancer Res 56:816–825

    CAS  Google Scholar 

  39. Combeau C, Commercon A, Mioskowski C, Rousseau B, Aubert F, Goeldner M (1994) Biochemistry 33:6676–6683

    Article  CAS  Google Scholar 

  40. Rao S, He L, Chakravarty S, Ojima I, Orr GA, Horwitz SB (1999) J Biol Chem 274:37990–37994

    Article  CAS  Google Scholar 

  41. Rao S, Krauss NE, Heerding JM, Orr GA, Horwitz SB (1994) J Biol Chem 269:3131–3134

    Google Scholar 

  42. Rao S, Orr GA, Chaudhary AG, Kingston DG, Horwitz SB (1995) J Biol Chem 270:20235–20238

    Article  CAS  Google Scholar 

  43. Lowe J, Li H, Downing KH, Nogales E (2001) J Mol Biol 313:1045–1057

    Article  CAS  Google Scholar 

  44. Nogales E, Wolf SG, Downing KH (1998) Nature 391:199–203

    Article  CAS  Google Scholar 

  45. Snyder JP, Nettles JH, Cornett B, Downing KH, Nogales E (2001) Proc Natl Acad Sci USA 98:5312–5316

    Article  CAS  Google Scholar 

  46. Ganesh T, Guza RC, Bane S, Ravindra R, Shanker N, Lakdawala AS, Snyder JP, Kingston DGI (2004) Proc Natl Acad Sci USA 101:10006–10011

    Article  CAS  Google Scholar 

  47. Yang Y, Alcaraz AA, Snyder JP (2009) J Nat Prod 72:422–429

    Article  CAS  Google Scholar 

  48. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Oncogene 22:7280–7295

    Article  CAS  Google Scholar 

  49. Geng X, Geney R, Pera P, Bernacki J, Ojima I (2004) Biorg Med Chem Lett 14:3491–3494

    Google Scholar 

  50. Clark M, Cramer RD, Opdenbosh NV (1989) Comput Chem 10:982–1012

    Article  CAS  Google Scholar 

  51. Tripos Inc. (2006) SYBYL Molecular Modeling System, 72nd edn. Tripos Inc., St Louis

  52. Xu SC, Deng S, Ma L, Shi Q, Ge M, Zhang X (2009) Active sites for retinal binding to bovine rhodopsin. Acta Phys Chem Sin 25:1290–1296

    CAS  Google Scholar 

  53. Becke AD (1993) J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  54. Lee C, Yang W, Parr RG (1988) Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  55. Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03, revision C.02. Gaussian Inc., Wallingford

  56. Berendsen HJC, Spoel DVD, Drunen RV (1995) Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  57. Spoel DVD, Lindahl E, Hess B, Buuren ARV, Apol E, Meulenhoff PJ, Tieleman DP, Sijbers ALTM, Feenstra KA, Drunen RCv, Berendsen HJ (2005) Gromacs user manual, version 3.2. http://www.gromacs.org

  58. Spoel DVD, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) J Comput Chem 26:1701–1718

    Article  CAS  Google Scholar 

  59. Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33–38

    Article  CAS  Google Scholar 

  60. van Gunsteren WF, Billeter SR, Eising AA, Hunenberger PH, Krueger P, Mark AE, Scott WRP, Tironi IG (1996) Biomolecular simulation: the Gromos 96 manual and user guide, 1st edn. Hochschulverlag AG, ETHC Zurich, Zurich

  61. Berendsen HJC, Postma JPM, Gunsteren WFv, Hermans J, Pullman B (2001) J Am Chem Soc 123:8638–8639

  62. Miyamoto S, Kollman PA (1992) J Comput Chem 13:952–962

    Article  CAS  Google Scholar 

  63. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  64. Berendsen HJC, Postma JPM, Gunsteren WF, Dinola A, Haak JR (1984) J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  65. Nettles JH, Li H, Cornett B, Krahn JM, Snyder JP, Downing KH (2004) Science 305:866–869

    Google Scholar 

  66. Ewing TJA, Kuntz ID (1997) J Comput Chem 18:1175–1189

    Article  CAS  Google Scholar 

  67. Lang PT, Moustakas D, Brozell S, Carrascal N, Mukherjee S, Pegg S, Raha K, Shivakumar D, Rizzo R, Case DA, Shoichet BK, Kuntz I (2006) DOCK 6.1. University of California, San Francisco

    Google Scholar 

  68. Cambria MT, Di Marino D, Falconi M, Garavaglia S, Cambria A (2010) J Biomol Struct Dyn 27:501–510

    CAS  Google Scholar 

  69. Da Cunha EFF, Barbosa EF, Oliveira AA, Ramalho TC (2010) J Biomol Struct Dyn 27:619–625

    Google Scholar 

  70. Huang HJ, Lee KJ, Yu HW, Chen CY, Hsu CH, Chen HY, Tsai FJ, Chen CYC (2010) J Biomol Struct Dyn 28:23–37

    CAS  Google Scholar 

  71. Nekrasov AN, Zinchenko AA (2010) J Biomol Struct Dyn 28:85–96

    CAS  Google Scholar 

  72. Tao Y, Rao ZH, Liu SQ (2010) J Biomol Struct Dyn 28:143–157

    CAS  Google Scholar 

  73. Kahlon AK, Roy S, Sharma A (2010) J Biomol Struct Dyn 28:201–210

    CAS  Google Scholar 

  74. Tuccinardi T, Botta M, Giordano A, Martinelli A (2010) J Chem Inf Model 50:1432–1441

    Article  CAS  Google Scholar 

  75. Li Y, Shen J, Sun X, Li W, Liu G, Tang Y (2010) J Chem Inf Model 50:1134–1146

    Article  CAS  Google Scholar 

  76. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

  77. Faver JC, Benson ML, He X, Roberts BP, Wang B, Marshall MS, Kennedy MR, Sherrill CD, Merz KM Jr (2011) J Chem Theor Comput 7:790–797

    Article  CAS  Google Scholar 

  78. Gilson MK, Zhou HX (2007) Annu Rev Biophys Biomol Struct 36:21–42

    Article  CAS  Google Scholar 

  79. Leach AR, Shoichet BK, Peishoff CE (2006) J Med Chem 49:5851–5855

    Article  CAS  Google Scholar 

  80. Merz KM (2010) J Chem Theor Comput 6:1769–1776

    Article  CAS  Google Scholar 

  81. Dill KA (1997) J Biol Chem 272:701–704

    CAS  Google Scholar 

  82. Hayik SA, Dunbrack R Jr, Merz KM Jr (2010) J Chem Theor Comput 6:3079–3091

    Article  CAS  Google Scholar 

  83. Lyne PD (2002) Drug Discov Today 7:1047–1055

    Article  CAS  Google Scholar 

  84. Jorgensen WL (2004) Science 303:1813–1818

    Article  CAS  Google Scholar 

  85. Abel R, Young T, Farid R, Berne BJ, Friesner RA (2008) J Am Chem Soc 130:2817–2831

    Article  CAS  Google Scholar 

  86. Moitessier N, Henry C, Maigret B, Chapleur Y (2004) J Med Chem 47:4178–4187

    Article  CAS  Google Scholar 

  87. Sutherland JJ, Nandigam RK, Erickson JA, Vieth M (2007) J Chem Inf Model 47:2293–2302

    Article  CAS  Google Scholar 

  88. Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Nat Rev Drug Discovery 3:935–949

    Article  CAS  Google Scholar 

  89. Lengauer T, Lemmen C, Rarey M, Zimmermann M (2004) Drug Discov Today 9:27–34

    Article  CAS  Google Scholar 

  90. Zhou T, Caflisch A (2010) Chem Med Chem 5:1007–1014

    CAS  Google Scholar 

  91. Raha K, Peters MB, Wang B, Yu N, Wollacott AM, Westerhoff LM, Merz KM (2007) Drug Discov Today 12:725–731

    Article  CAS  Google Scholar 

  92. Peters MB, Raha K, Merz KM (2006) Curr Opin Drug Discov Dev 9:370–379

    CAS  Google Scholar 

  93. Raha K, Merz KM (2005) J Med Chem 48:4558–4575

    Article  CAS  Google Scholar 

  94. Fukuzawa K, Kitaura K, Uebayasi M, Nakata K, Kaminuma T, Nakano T (2005) J Comput Chem 26:1–10

    Article  CAS  Google Scholar 

  95. Clark RD, Strizhev A, Leonard JM, Blake JF, Matthew JB (2002) J Mol Graph Model 20:281–295

    Article  CAS  Google Scholar 

  96. Bohm HJ (1998) J Comput-Aided Mol Des 12:309–323

    Article  CAS  Google Scholar 

  97. Wang R, Lu Y, Wang S (2003) J Med Chem 46:2287–2303

    Article  CAS  Google Scholar 

  98. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Proteins Struct Funct Genet 52:609–623

    Article  CAS  Google Scholar 

  99. Trott O, Olson AJ (2009) J Comput Chem 31:455–461

    Google Scholar 

  100. Capel-Sanchez MC, de la Peña-O’Shea VA, Barrio L, Campos-Martin JM, Fierro JLG (2006) Top Catal 41:1–4

    Google Scholar 

  101. Cramer CJ, Tolman WB, Theopolid KH, Rheingold AL (2003) Proc Natl Acad Sci USA 100:3635–3640

    Article  CAS  Google Scholar 

  102. Mitra S, Singh TS, Mandal A, Mukherjee S (2007) Chem Phys 342:309–317

    Article  CAS  Google Scholar 

  103. Rao L, Ke HW, Fu G (2009) J Chem Theor Comput 5:86–96

    Article  CAS  Google Scholar 

  104. Główka ML, Martynowski D, Kozłowska K (1999) J Mol Struct 474:81–89

    Article  Google Scholar 

  105. Huang JS, Kertesz M (2007) J Phys Chem A 111:6304–6315

    Article  CAS  Google Scholar 

  106. Kim KS, Suh SB, Kim JC, Hong BH, Lee EC, Yun S, Arakeshwar P, Lee JY, Kim Y, Ihm H, Kim HG, Lee JW, Kim JK, Lee HM, Kim D, Cui C, Youn SJ, Chung HY, Choi HS, Lee CW, Cho SJ, Jeong S, Cho JH (2002) J Am Chem Soc 124:14268–14279

    Article  CAS  Google Scholar 

  107. Pablo PJD, Moreno-Herrero F, Colchero J, Herrero JG, Baro AM, Ordejon P, Soler JM, Artacho E (2000) Phys Rev Lett 85:4992–4995

    Article  Google Scholar 

  108. Sun CL, Wang CS (2009) Chin Sci B 39:481–487

    Google Scholar 

  109. Szekeres ZS, Bogár F, Ladik J (2005) Int J Quant Chem 102:422–426

    Google Scholar 

  110. Zhang SG, Zhang LC, Yang P (2008) Acta Phys Chim Sin 24:1637–1642

    CAS  Google Scholar 

  111. Boys SF, Bernardi F (1970) Mol Phys 19:553–556

    Article  CAS  Google Scholar 

  112. Bene JED (1993) J Phys Chem 97:107–110

    Article  Google Scholar 

  113. van Duijneveldt FB, van de Rijdt JGCM, van Lenthe JH (1994) Chem Rev 94:1873–1885

    Article  Google Scholar 

  114. Kryachko ES, Zeegers-Huyskens T (2002) J Phys Chem A 106:6832–6838

    Article  CAS  Google Scholar 

  115. Xu SC, Ma LY, Bian FY, Shi Q, Ge MF, Zhang XK (2009) Acta Phys Chim Sin 25:2312–2318

    CAS  Google Scholar 

  116. Xu SC, Deng SR, Ma LY, Shi Q, Ge MF, Zhang XK (2010) Int J Quant Chem 110:2671–2682

    Google Scholar 

  117. Wang Y, Bian FY, Deng SR, Shi Q, Ge MF, Wang S, Zhang XK, Xu SC (2011) J Biomol Struct Dyn 28:881–893

    CAS  Google Scholar 

  118. Ruf A, Mennissier de Murcia J, de Murcia G, Schulz GE (1996) Proc Natl Acad Sci USA 93:7481–7485

    Google Scholar 

  119. Ruf A, de Murcia G, Schulz GE (1998) Biochemistry 37:3893–3900

    Google Scholar 

  120. Kingston DGI (2000) J Nat Prod 63:726–734

    Article  CAS  Google Scholar 

  121. Ganesh T, Yang C, Norris A, Glass T, Bane S, Ravindra R, Banerjee A, Metaferia B, Thomas SL, Giannakakou P, Alcaraz AA, Lakdawala AS, Snyder JP, Kingston DGI (2007) J Med Chem 50:713–725

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by One-Hundred-Talents Project of Chinese Academy of Sciences, and the Academic Talent Foundation of Yunnan Province, China (2006PY01-29).

Author information

Authors and Affiliations

  1. Key Laboratory of Education Ministry for Medicinal Chemistry of Natural Resource, College of Chemical Science and Technology, Yunnan University, Kunming, 650091, People’s Republic of China

    Sichuan Xu, Shaoming Chi & Yi Jin

  2. State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, People’s Republic of China

    Sichuan Xu, Qiang Shi, Maofa Ge, Shu Wang & Xingkang Zhang

Authors
  1. Sichuan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaoming Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maofa Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xingkang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sichuan Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, S., Chi, S., Jin, Y. et al. Molecular dynamics simulation and density functional theory studies on the active pocket for the binding of paclitaxel to tubulin. J Mol Model 18, 377–391 (2012). https://doi.org/10.1007/s00894-011-1083-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-011-1083-7

Keywords

Search

Navigation