title: The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies.
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.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Magnani
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Simonetta
authors.initials: S
authors.lastname: Soro
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000465:Algorithms; D050256:Antimitotic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D034261:Epothilones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D012984:Software; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050256:Antimitotic Agents; D000972:Antineoplastic Agents, Phytogenic; D034261:Epothilones; D008024:Ligands; D020033:Protein Isoforms; D014404:Tubulin; D017239:Paclitaxel