tailieunhanh - Báo cáo khoa học: The bI/bIII-tubulin isoforms and their complexes with antimitotic agents

Both microtubule destabilizer and stabilizer agents are important molecules in anticancer therapy. In particular, paclitaxel has been demonstrated to be effective for the treatment of ovarian, breast, and nonsmall cell lung carci-nomas. It has been shown that emergence of resistance against this agent correlates with an increase in the relative abundance of tubulin isoform bIII and that the more recently discovered IDN5390 can be effectively used once resistance has emerged. | ềFEBS Journal The pi piii-tubulin isoforms and their complexes with antimitotic agents Docking and molecular dynamics studies Matteo Magnani1 Francesco Ortuso2 Simonetta Soro3 Stefano Alcaro2 Anna Tramontano3 and Maurizio Botta1 1 Dipartimento Farmaco Chimico Tecnologico Universita degli Studi di Siena Italy 2 Dipartimento di Scienze Farmacobiologiche Complesso Nin Barbieri Universita degli Studi di Catanzaro Magna Graecia Roccelletta di Borgia CZ Italy 3 Dipartimento di Scienze Biochimiche A. Rossi Fanelli Universita degli Studi La Sapienza Rome Italy Keywords docking epothilone A IDN5390 paclitaxel tubulin Correspondence M. Botta Dipartimento Farmaco Chimico Tecnologico University degli Studi di Siena Via Alcide de Gasperi 2 I-53100 Siena Italy Fax 39 577 234333 Tel 39 577 234306 E-mail botta@ Received 7 April2006 revised 16 May 2006 accepted 23 May 2006 doi Both microtubule destabilizer and stabilizer agents are important molecules in anticancer therapy. In particular paclitaxel has been demonstrated to be effective for the treatment of ovarian breast and nonsmall cell lung carcinomas. It has been shown that emergence of resistance against this agent correlates with an increase in the relative abundance of tubulin isoform bIII and that the more recently discovered IDN5390 can be effectively used once resistance has emerged. In this paper we analyze the binding modes of these antimitotic agents to type I and III isoforms of b-tubulin by computational methods. Our results are able to provide a molecular explanation of the experimental data. Using the same protocol we could also show that no preference for any of the two isoforms can be detected for epothilone A a potentially very interesting drug for which no data about the emergence of resistance is currently available. Our analysis provides structural insights about the recognition mode and the stabilization mechanism of these antimitotic agents and provides useful .

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