Molecular Biology

, Volume 52, Issue 4, pp 604–608 | Cite as

In silico Search for Tubulin Polymerization Inhibitors

  • H. K. Sahakyan
  • G. G. Arakelov
  • K. B. Nazaryan
Structural Functional Analysis Of Biopolymers and Their Complexes


Cytostatic colchicine is widely used in the treatment of Familial Mediterranean fever, but it has several side effects. For finding new, more effective drugs with higher affinity and diminishside effects we carried out virtual screening of potential inhibitors of the main target of colchicine, the polymerization of tubulin by evaluating affinity 25745 compounds, structurally related to the colchicine. We have identified 11 commercially available compounds with higher affinity to tubulin. Compounds with highest binding scores include trimethoxybenzene and its derivatives; these compounds bind to the same site in similar orientation. Information provided can form the basis for design of new cytostatics.


virtual ligand screening colchicine binding site tubulin inhibitors 



Colchicine Binding Site


Compound Identifier


Familial Mediterranean Fever


Internal Coordinates Mechanics


Microtubule-Associated Proteins


Structure-Activity Relationships


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  1. 1.
    Coakley W.T. 1987. Hyperthermia effects on the cytoskeleton and on cell morphology. Symp. Soc. Exp. Biol. 41, 187–211.PubMedGoogle Scholar
  2. 2.
    Menéndez M., Rivas G., Díaz J.F., Andreu J.M. 1998. Control of the structural stability of the tubulin dimer by one high affinity bound magnesium ion at nucleotide N-site. J. Biol. Chem. 273 (1), 167–176.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang R., Alushin G.M., Brown A., Nogales E. 2015. Mechanistic origin of microtubule dynamic instability and its modulation by EBproteins. Cell. 162 (4), 849–859.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Weisenberg R.C., Broisy G.G., Taylor E.W. 1968. Colchicine-binding protein of mammalian brain and its relation to microtubules. Biochemistry. 7 (12), 4466–4479.CrossRefPubMedGoogle Scholar
  5. 5.
    Panda D., Daijo J.E., Jordan M.A., Wilson L. 1995. Kinetic stabilization of microtubule dynamics at steady state in vitro by substoichiometric concentrations of tubulin-colchicine complex. Biochemistry. 34 (31), 9921–9929.CrossRefPubMedGoogle Scholar
  6. 6.
    Prota A.E., Bargsten K., Zurwerra D., Field J.J., Díaz J.F., Altmann K.H., Steinmetz M.O. 2013. Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science. 339 (6119), 587–590.CrossRefPubMedGoogle Scholar
  7. 7.
    Jordan M.A., Wilson L. 2004. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer. 4 (4), 253–265.CrossRefPubMedGoogle Scholar
  8. 8.
    Lu Y., Chen J., Xiao M., Li W., Miller D.D. 2012. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res. 29 (11), 2943–2971.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ravelli R.B., Gigant B., Curmi P.A., Jourdain I., Lachkar S., Sobel A., Knossow M. 2004. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 428 (6979), 198–202.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu W., Sun P., Yang L., Wang J., Li L., Wang J. 2010. Assay of glioma cell responses to an anticancer drug in a cell-based microfluidic device. Microfluidics Nanofluidics. 9 (4–5), 717–725.CrossRefGoogle Scholar
  11. 11.
    Cho J.H., Joo Y.H., Shin E.Y., Park E.J., Kim M.S. 2017. Anticancer effects of colchicine on hypopharyngeal cancer. Anticancer Res. 37 (11), 6269–6280.PubMedGoogle Scholar
  12. 12.
    Lidar M., Livneh A. 2007. Familial Mediterranean fever: Clinical, molecular and management advancements. Neth. J. Med. 65 (9), 318–324.PubMedGoogle Scholar
  13. 13.
    Emmerson B.T. 1996. The management of gout. New Engl. J. Med. 334 (7), 445–451.CrossRefPubMedGoogle Scholar
  14. 14.
    Deursen R.V., Blum L.C., Reymond J.L. 2010. A searchable map of PubChem. J. Chem. Inform. Modeling. 50 (11), 1924–1934.CrossRefGoogle Scholar
  15. 15.
    Prota A.E., Danel F., Bachmann F., Bargsten K., Buey R.M., Pohlmann J., Reinelt S., Lane H., Steinmetz M.O. 2014. The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization. J. Mol. Biol. 426 (8), 1848–1860.CrossRefPubMedGoogle Scholar
  16. 16.
    Marangon J., Christodoulou M.S., Casagrande F.V., Tiana G., Dalla Via L., Aliverti A., Passarella D., Cappelletti G., Ricagno S. 2016. Tools for the rational design of bivalent microtubule-targeting drugs. Biochem. Biophys. Res. Commun. 479 (1), 48–53.CrossRefPubMedGoogle Scholar
  17. 17.
    Gaspari R., Prota A. E., Bargsten K., Cavalli A., Steinmetz M.O. 2017. Structural basis of cis-and trans-combretastatin binding to tubulin. Chem. 2 (1), 102–113.CrossRefGoogle Scholar
  18. 18.
    Bottegoni G., Kufareva I., Totrov M., Abagyan R. 2009. Four-dimensional docking: A fast and accurate account of discrete receptor flexibility in ligand docking. J. Med. Chem. 52 (2), 397–406.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Totrov M. 2011. Ligand binding site superposition and comparison based on atomic property fields: Identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites. BMC Bioinformatics. 12 (1), 35.CrossRefGoogle Scholar
  20. 20.
    Sadovnichy V., Tikhonravov A., Voevodin V., Opanasenko V. 2013. “Lomonosov”: Supercomputing at Moscow State University. Contemporary High Performance Computing: From Petascale toward Exascale. Chapman & Hall/CRC Computational Science, Boca Raton, FL: CRC Press, pp. 283–307.Google Scholar
  21. 21.
    Kaur R., Kaur G., Gill R.K., Soni R., Bariwal J. 2014. Recent developments in tubulin polymerization inhibitors: An overview. Eur. J. Med. Chem. 87, 89–124.CrossRefPubMedGoogle Scholar
  22. 22.
    Olazarán F.E., García-Pérez C.A., Bandyopadhyay D., Balderas-Rentería I., Reyes-Figueroa A.D., Henschke L., Rivera G. 2017. Theoretical and experimental study of polycyclic aromatic compounds as β-tubulin inhibitors. J. Mol. Model. 23 (3), 85.CrossRefPubMedGoogle Scholar
  23. 23.
    Nogales E., Wolf S.G., Downing K.H. 1998. Structure of the αβ tubulin dimer by electron crystallography. Nature. 391 (6663), 199–203.CrossRefPubMedGoogle Scholar
  24. 24.
    Varzhabetyan L.R., Glazachev D.V., Nazaryan K.B. 2012. Molecular dynamics simulation study of tubulin dimer interaction with cytostatics. Mol. Biol. (Moscow). 46 (2), 316–321.CrossRefGoogle Scholar
  25. 25.
    Nepali K., Ojha R., Sharma S., Bedi P., Dhar K. 2014. Tubulin inhibitors: A patent survey. Recent Pat. Anticancer Drug Discov. 9 (2), 176–220.CrossRefPubMedGoogle Scholar
  26. 26.
    Chaudhary V., Venghateri J.B., Dhaked H.P., Bhoyar A.S., Guchhait S.K., Panda D. 2016. Novel combretastatin-2-aminoimidazole analogues as potent tubulin assembly inhibitors: Exploration of unique pharmacophoric impact of bridging skeleton and aryl moiety. J. Med. Chem. 59 (7), 3439–3451.CrossRefPubMedGoogle Scholar
  27. 27.
    Salum L.B., Altei W.F., Chiaradia L.D., Cordeiro M.N., Canevarolo R.R., Melo C.P., Winter E., Mattei B., Daghestani H.N., Santos-Silva M.C., Creczynski-Pasa T.B., Yunes R.A., Yunes J.A., Andricopulo A.D., Day B.W., et al. 2013. Cytotoxic3,4,5-trimethoxychalcones as mitotic arresters and cell migration inhibitors. Eur. J. Med. Chem. 63, 501–510.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • H. K. Sahakyan
    • 1
    • 2
  • G. G. Arakelov
    • 1
    • 2
  • K. B. Nazaryan
    • 1
    • 2
  1. 1.Russian–Armenian UniversityYerevanArmenia
  2. 2.Institute of Molecular BiologyNational Academy of Sciences of the Republic of ArmeniaYerevanArmenia

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