| Abstract | 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 betaIII 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 beta-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 suggestions for the design of more potent and selective antimitotic agents. |
| Authors | Matteo Magnani, Francesco Ortuso, Simonetta Soro, Stefano Alcaro, Anna Tramontano, Maurizio Botta
(Affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Italy.)
|
| Journal | The FEBS journal
(FEBS J)
Vol. 273
Issue 14
Pg. 3301-10
(Jul 2006)
ISSN: 1742-464X England |
| PMID | 16803461
(Publication Type: Comparative Study, Journal Article)
|
| Chemical References |
- Antimitotic Agents
- Antineoplastic Agents, Phytogenic
- Epothilones
- Ligands
- Protein Isoforms
- Tubulin
- Paclitaxel
|
| Topics |
- Algorithms
- Antimitotic Agents
(chemistry, metabolism, pharmacology)
- Antineoplastic Agents, Phytogenic
(chemistry, metabolism, pharmacology)
- Binding Sites
- Computational Biology
- Computer Simulation
- Crystallography, X-Ray
- Epothilones
(chemistry, metabolism, pharmacology)
- Humans
- Hydrogen Bonding
- Ligands
- Models, Molecular
- Molecular Structure
- Paclitaxel
(chemistry, metabolism, pharmacology)
- Protein Binding
- Protein Isoforms
(chemistry, metabolism)
- Protein Structure, Secondary
- Software
- Thermodynamics
- Tubulin
(chemistry, metabolism)
|
