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2011 | 58 | 2 | 255-260
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Computational study of binding of epothilone A to β-tubulin

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Understanding the interactions of epothilones with β-tubulin is crucial for computer aided rational design of macrocyclic drugs based on epothilones and epothilone derivatives. Despite numerous structure-activity relationship investigations we still lack substantial knowledge about the binding mode of epothilones and their derivatives to β-tubulin. In this work, we reevaluated the electron crystallography structure of epothilone A/β-tubulin complex (PDB entry 1TVK) and proposed an alternative binding mode of epothilone A to β-tubulin that explains more experimental facts.
Physical description
  • Laboratory of Theory of Biopolymers, Faculty of Chemistry, University of Warsaw, Warszawa, Poland
  • Laboratory of Theory of Biopolymers, Faculty of Chemistry, University of Warsaw, Warszawa, Poland
  • Altmann K-H, Bold G, Caravatti G, Flörsheimer A, Guagnano V, Wartmann M (2000) Synthesis and biological evaluation of highly potent analogues of epothilones B and D. Bioorg Med Chem Lett 10: 2765-2768.
  • Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J, Goetz M, Lazarides E, Woods CM (1995) Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res 55: 2325-2333.
  • Carlomagno T, Blommers MJJ, Meiler J, Jahnke W, Schupp T, Petersen F, Schinzer D, Altmann K-H, Griesinger C (2003) The high-resolution solution structure of epothilone A bound to tubulin: an understanding of the structure-activity relationships for a powerful class of antitumor agents. Angew Chem Int Ed Engl 42: 2511-2515.
  • Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM Jr, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A 2nd generation force field for the simulation of proteins, nucleic-acids and organic molecules. J Am Chem Soc 117: 5179-5197.
  • De Jonge M, Verweij J (2005) The epothilone dilemma. J Clin Oncol 23: 9048-9050.
  • Fanfrlík J, Bronowska AK, Rezac J, Prenosil O, Konvalinka J, Hobza P (2010) A reliable docking/scoring scheme based on the semiempirical quantum mechanical PM6-DH2 method accurately covering dispersion and H-bonding: HIV-1 protease with 22 ligands. J Phys Chem B 114: 12666-12678.
  • Gerth K, Bedorf N, Höfle G, Irschik H, Reichenbach H (1996) Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria) - Production, physic-chemical and biological properties. J Antibiot 49: 560-563.
  • Heinz DW, Schubert W-D, Höfle G (2005) Much anticipated - The bioactive conformation of epothilone and its binding to tubulin. Angew Chem Int Ed Engl 44: 1298-1301.
  • Höfle G, Bedorf N, Gerth K, Reichenbach H (1993) DE-4138042. Chem Abstr 120: 52841.
  • Johnson J, Kim S-H, Bifano M, DiMarco J, Fairchild C, Gougoutas J, Lee F, Long B, Tokarski J, Vite G (2000) Synthesis, structure proof, and biological activity of epothilone cyclopropanes. Org Lett 2: 1537-1540.
  • Klamt A, Schuurmann G (1993) COSMO - a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient. J Chem Soc Perkin Trans 2: 799-805.
  • Korth M, Pitonak M, Rezac J, Hobza P (2010) A Transferable H_Bonding Correction for Semiempirical Quantum-Chemical Methods. J Chem Theory Comput 6: 344-352.
  • Löwe J, Li H, Downing KH, Nogales E (2001) Refined structure of αβ-tubulin at 3.5 Å resolution. J Mol Biol 313: 1045-1057.
  • Makowski L (1995) Electron crystallography. Taxol found on tubulin. Nature 375: 361-362.
  • Morris GM, Goodsell DS, Halliday RS, Huey R, Hart J, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19: 1639-1662.
  • Nettles JH, Li H, Cornett B, Krahn JM, Snyder JP, Downing KH (2004) The binding mode of epothilone a on α,β-tubulin by electron crystallography. Science 305: 866-869.
  • Nicolaou KC, Namoto K, Ritzén A, Ulven T, Shoji M, Li J, D'Amico G, Liotta D, French CT, Wartmann M, Altmann K-H, Giannakakou P (2001) Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues. J Am Chem Soc 123: 9313-9323.
  • Nicolaou KC, Ritzén A, Namoto K, Buey RM, Diáz JF, Andreu JM, Wartmann M, Altmann K-H, O'Brate A, Giannakakou P (2002) Chemical synthesis and biological evaluation of novel epothilone B and trans-12,13-cyclopropyl epothilone B analogues. Tetrahedron 58: 6413-6432.
  • Nicolaou KC, Scarpelli R, Bollbuck B, Werschkun B, Pereira MMA, Wartmann M, Altmann K-H, Zaharevitz D, Gussio R, Giannakakou P (2000) Chemical synthesis and biological properties of pyridine epothilones. Chem Biol 7: 593-599.
  • Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera - a visualization system for exploratory research and analysis. J Comput Chem 25: 1605-1612.
  • Raha K, Merz KM Jr (2005) Large-scale validation of a quantum mechanics based scoring function: predicting the binding affinity and the binding mode of a diverse set of portein-ligand complexes. J Med Chem 48: 4558-4575.
  • Regueiro-Ren A, Borzilleri RM, Zheng X, Kim S-H, Johnson JA, Fairchild CR, Lee FYF, Long BH, Vite GD (2001) Synthesis and biological activity of novel epothilone aziridines. Org Lett 3: 2693-2696.
  • Regueiro-Ren A, Leavitt K, Kim S-H, Höfle G, Kiffe M, Gougoutas JZ, DiMarco JD, Lee FYF, Fairchild CR, Long BH, Vite GD (2002) SAR and pH stability of cyano-substituted epothilones. Org Lett 4: 3815-3818.
  • Stewart JJP (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13: 1173-1213.
  • Stewart JJP (2008) Stewart Computational Chemistry, Colorado Springs, CO, MOPAC2009;
  • Wang M, Xia X, Kim Y, Hwang D, Jansen JM, Botta M, Liotta DC, Snyder JP (1999) A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone. Org Lett 1: 43-46.
  • Wartmann M, Altmann K-H (1996) The biology and medicinal chemistry of epothilones. Curr Med Chem Anti Cancer Agents 2: 123-148.
  • Zhan W, Jiang Y, Brodie PJ, Kingston DGI, Liotta DC, Snyder JP (2008) Design and synthesis of C6−C8 bridged epothilone A. Org Lett 10: 1565-1568.
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