Journal of Computer-Aided Molecular Design

, Volume 24, Issue 1, pp 1–15 | Cite as

Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

  • Abrar Hussain
  • James L. Melville
  • Jonathan D. Hirst


Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide ‘tail’ to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q 2 value of 0.85 and a r 2 of 0.94. Results from the docking simulations and the interpretation from QSAR “coeff*stdev” contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.


Aplyronine A Macrolides F-actin depolymerisation 3D-QSAR AutoDock 



We thank Craig Bruce for advice and useful discussions.

Supplementary material

10822_2009_9307_MOESM1_ESM.pdf (62 kb)
PDF (61 KB)


  1. 1.
    Sheterline P, Clayton J, Sparrow JC (1998) Actin, 4th edn. Oxford University Press, New YorkGoogle Scholar
  2. 2.
    Carlier MF (1998) Control of actin dynamics. Curr Opin Cell Biol 10:45–51CrossRefGoogle Scholar
  3. 3.
    Carlier MF, Pantaloni D (1997) Control of actin dynamics in cell motility. J Mol Biol 269:459–467CrossRefGoogle Scholar
  4. 4.
    Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–465CrossRefGoogle Scholar
  5. 5.
    Westphal M, Jungbluth A, Heidecker M, Mühlbauer B, Heizer C, Schwartz JM, Marriott G, Gerisch G (1997) Microfilament dynamics during cell movement and chemotaxis monitored using a GFP-actin fusion protein. Curr Biol 7:176–183CrossRefGoogle Scholar
  6. 6.
    Pollard TD, Cooper JA (1986) Actin and actin-binding proteins: a critical evaluation of mechanisms and functions. Ann Rev Biochem 55:987–1035CrossRefGoogle Scholar
  7. 7.
    dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, Berry DA, Nosworthy NJ (2003) Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol Rev 83:433–473Google Scholar
  8. 8.
    Stossel TP (1989) From signal to pseudopod. How cells control cytoplasmic actin assembly. J Biol Chem 264:18261–18264Google Scholar
  9. 9.
    Lambrechts A, Van Troys M, Ampe C (2004) The actin cytoskeleton in normal and pathological cell motility. Int J Biochem Cell Biol 36:1890–1909CrossRefGoogle Scholar
  10. 10.
    Allingham JS, Klenchin VA, Rayment I (2006) Actin-targeting natural products: structures, properties and mechanisms of action. Cell Mol Life Sci 63:2119–2134CrossRefGoogle Scholar
  11. 11.
    Button E, Shapland C, Lawson D (1995) Actin, its associated proteins and metastasis. Cell Motil Cytoskelet 30:247–251CrossRefGoogle Scholar
  12. 12.
    Giganti A, Friederich E (2003) The actin cytoskeleton as a therapeutic target: state of the art and future directions. Prog Cell Cycle Res 5:511–525Google Scholar
  13. 13.
    Jordan MA, Wilson L (1998) Microtubules and actin filaments: dynamic targets for cancer chemotherapy. Curr Opin Cell Biol 10:123–130CrossRefGoogle Scholar
  14. 14.
    Yeung KS, Paterson I (2002) Actin-binding marine macrolides: total synthesis and biological importance. Angew Chem Int Ed Engl 41:4632–4653CrossRefGoogle Scholar
  15. 15.
    Klenchin VA, Allingham JS, King R, Tanaka J, Marriott G, Rayment I (2003) Trisoxazole macrolide toxins mimic the binding of actin-capping proteins to actin. Nat Struct Biol 10:1058–1063CrossRefGoogle Scholar
  16. 16.
    Spector I, Braet F, Shochet NR, Bubb MR (1999) New anti-actin drugs in the study of the organization and function of the actin cytoskeleton. Microsc Res Tech 47:18–37CrossRefGoogle Scholar
  17. 17.
    Tanaka J, Yan Y, Choi J, Bai J, Klenchin VA, Rayment I, Marriott G (2003) Biomolecular mimicry in the actin cytoskeleton: mechanisms underlying the cytotoxicity of kabiramide C and related macrolides. Proc Natl Acad Sci USA 100:13851–13856CrossRefGoogle Scholar
  18. 18.
    Tanaka J, Blain JC, Allingham JS (2008) Actin-binding toxin “tail” wags the dog. Chem Biol 15:205–207CrossRefGoogle Scholar
  19. 19.
    Hirata K, Muraoka S, Suenaga K, Kuroda T, Kato K, Tanaka H, Yamamoto M, Takata M, Yamada K, Kigoshi H (2006) Structure basis for antitumor effect of aplyronine A. J Mol Biol 356:945–954CrossRefGoogle Scholar
  20. 20.
    Kigoshi H, Suenaga K, Takagi M, Akao A, Kanematsu K, Kamei N, Okugawa Y, Yamada K (2002) Cytotoxicity and actin-depolymerizing activity of aplyronine A, a potent antitumor macrolide of marine origin, and its analogs. Tetrahedron 58:1075–1102CrossRefGoogle Scholar
  21. 21.
    D’Auria MV, Paloma LG, Minale L, Zampella A, Verbist JF, Roussakis C, Debitus C, Patissou J (1994) Reidispongiolide A and B, two new potent cytotoxic macrolides from the New Caledonian sponge Reidispongia coerulea. Tetrahedron 50:4829–4834CrossRefGoogle Scholar
  22. 22.
    Allingham JS, Tanaka J, Marriott G, Rayment I (2004) Absolute stereochemistry of ulapualide A. Org Lett 6:597–599CrossRefGoogle Scholar
  23. 23.
    Roesener JA, Scheuer PJ (1986) Ulapualide A and B, extraordinary antitumor macrolides from nudibranch eggmasses. J Am Chem Soc 108:846–847CrossRefGoogle Scholar
  24. 24.
    Yamada K, Ojika M, Ishigaki T, Yoshida Y, Ekimoto H, Arakawa M (1993) Aplyronine A, a potent antitumor substance, and the congeners aplyronine B and C isolated from the sea hare Aplysia kurodai. J Am Chem Soc 115:11020–11021CrossRefGoogle Scholar
  25. 25.
    Suenaga K, Kamei N, Okugawa Y, Takagi M, Akao A, Kigoshi H (1997) Cytotoxicity and actin depolymerizing activity of aplyronine A, a potent antitumor macrolide of marine origin, and the natural and artificial analogs. Bioorg Med Chem Lett 7:269–274CrossRefGoogle Scholar
  26. 26.
    Saito S, Watabe S, Ozaki H, Kigoshi H, Yamada K, Fusetani N, Karaki H (1996) Novel actin depolymerizing macrolide aplyronine A. J Biochem 120:552–555Google Scholar
  27. 27.
    Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37:4130–4146CrossRefGoogle Scholar
  28. 28.
    Burtnick LD, Koepf EK, Grimes J, Jones EY, Stuart DI, McLaughlin PJ, Robinson RC (1997) The crystal structure of plasma gelsolin: implications for actin severing, capping, and nucleation. Cell 90:661–670CrossRefGoogle Scholar
  29. 29.
    Sun HQ, Yamamoto M, Mejillano M, Yin HL (1999) Gelsolin, a multifunctional actin regulatory protein. J Biol Chem 274:33,179–33182Google Scholar
  30. 30.
    Spartan (2008) Wavefunction Inc., IrvineGoogle Scholar
  31. 31.
    Halgren T (1996) Merck molecular force field: I–V. J Comp Chem 17:490–641CrossRefGoogle Scholar
  32. 32.
    Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228CrossRefGoogle Scholar
  33. 33.
    Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17:57–61Google Scholar
  34. 34.
    Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiemirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152CrossRefGoogle Scholar
  35. 35.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662CrossRefGoogle Scholar
  36. 36.
    Melville JL, Moal IH, Baker-Glenn C, Shaw PE, Pattenden G, Hirst JD (2007) The structural determinants of macrolide-actin binding: in silico insights. Biophys J 92:3862–3867CrossRefGoogle Scholar
  37. 37.
    Bottoms CA, White TA, Tanner JJ (2006) Exploring structurally conserved solvent sites in protein families. Proteins 64:404–421CrossRefGoogle Scholar
  38. 38.
    Ogata K, Wodak SJ (2002) Conserved water molecules in MHC class-I molecules and their putative structural and functional roles. Protein Eng 15:697–705CrossRefGoogle Scholar
  39. 39.
    Roberts BC, Mancera RL (2008) Ligand-protein docking with water molecules. J Chem Inf Model 48:397–408CrossRefGoogle Scholar
  40. 40.
    Shaltiel S, Cox S, Taylor SS (1998) Conserved water molecules contribute to the extensive network of interactions at the active site of protein kinase A. Proc Natl Acad Sci USA 95:484–491CrossRefGoogle Scholar
  41. 41.
    Szybki Version 1.1.2 (2008) OpenEye Scientific Software Inc., Santa FeGoogle Scholar
  42. 42.
    Wildman SA, Crippen GM (1999) Prediction of physicochemical parameters by atomic contributions. J Chem Inf Comput Sci 39:868–873Google Scholar
  43. 43.
    Hou TJ, Xia K, Zhang W, Xu XJ (2004) ADME evaluation in drug discovery. 4. Prediction of aqueous solubility based on atom contribution approach. J Chem Inf Comput Sci 44:266–275Google Scholar
  44. 44.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38CrossRefGoogle Scholar
  45. 45.
    Cole JC, Murray CW, Nissink JW, Taylor RD, Taylor R (2005) Comparing protein-ligand docking programs is difficult. Proteins 60:325–332CrossRefGoogle Scholar
  46. 46.
    Wada S, Matsunaga S, Saito S, Fusetani N, Watabe S (1998) Actin-binding specificity of marine macrolide toxins, mycalolide B and kabiramide D. J Biochem 123:946–952Google Scholar
  47. 47.
    Perkins R, Fang H, Tong W, Welsh WJ (2003) Quantitative structure-activity relationship methods: perspectives on drug discovery and toxicology. Environ Toxicol Chem 22:1666–1679CrossRefGoogle Scholar
  48. 48.
    Rücker C, Rücker G, Meringer M (2007) y-randomization and its variants in QSPR/QSAR. J Chem Inf Model 47:2345–2357CrossRefGoogle Scholar
  49. 49.
    Wold S, Eriksson L (1995) In: van de Waterbeemd H (ed) Chemometric methods in molecular design. Wiley-VCH, Weinheim, pp 309–318Google Scholar
  50. 50.
    Yamada K, Ojika M, Kigoshi H, Suenaga K (2009) Aplyronine A, a potent antitumour macrolide of marine origin, and the congeners aplyronines B–H: chemistry and biology. Nat Prod Rep 26:27–43CrossRefGoogle Scholar
  51. 51.
    Kitamura K, Teruya T, Kuroda T, Kigoshi H, Suenaga K (2009) Synthesis of actin-depolymerizing compounds. Bioorg Med Chem Lett 19:1896–1898CrossRefGoogle Scholar
  52. 52.
    Perrins RD, Cecere G, Paterson I, Marriott G (2008) Synthetic mimetics of actin-binding macrolides: rational design of actin-targeted drugs. Chem Biol 15:287–294CrossRefGoogle Scholar
  53. 53.
    Leach AR, Shoichet BK, Peishoff CE (2006) Prediction of protein-ligand interactions. Docking and scoring: successes and gaps. J Med Chem 49:5851–5855CrossRefGoogle Scholar
  54. 54.
    Warren GL, Andrews CW, Capelli A-M, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) A critical assessment of docking programs and scoring functions. J Med Chem 49:5912–5931CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Abrar Hussain
    • 1
  • James L. Melville
    • 2
  • Jonathan D. Hirst
    • 1
  1. 1.School of ChemistryUniversity of NottinghamNottinghamUK
  2. 2.Cresset BioMolecular Discovery Ltd., BioPark HertfordshireHertfordshireUK

Personalised recommendations