title: Evaluation of the tubulin-bound paclitaxel conformation: synthesis, biology, and SAR studies of C-4 to C-3' bridged paclitaxel analogues.
abstract: The important anticancer drug paclitaxel binds to the beta-subunit of the alphabeta-tubulin dimer in the microtubule in a stoichiometric ratio, promoting microtubule polymerization and stability. The conformation of microtubule-bound drug has been the subject of intense study, and various suggestions have been proposed. In previous work we presented experimental and theoretical evidence that paclitaxel adopts a T-shaped conformation when it is bound to tubulin. In this study we report additional experimental data and calculations that delineate the allowable parameters for effective paclitaxel-tubulin interactions.
authors.affiliation: Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
authors.forename: Thota
authors.initials: T
authors.lastname: Ganesh
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Andrew
authors.initials: A
authors.lastname: Norris
authors.forename: Tom
authors.initials: T
authors.lastname: Glass
authors.forename: Susan
authors.initials: S
authors.lastname: Bane
authors.forename: Rudravajhala
authors.initials: R
authors.lastname: Ravindra
authors.forename: Abhijit
authors.initials: A
authors.lastname: Banerjee
authors.forename: Belhu
authors.initials: B
authors.lastname: Metaferia
authors.forename: Shala L
authors.initials: SL
authors.lastname: Thomas
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.forename: Ana A
authors.initials: AA
authors.lastname: Alcaraz
authors.forename: Ami S
authors.initials: AS
authors.lastname: Lakdawala
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: David G I
authors.initials: DG
authors.lastname: Kingston
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012996:Solutions; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D047029:Lactams, Macrocyclic; D012996:Solutions; D014404:Tubulin; D017239:Paclitaxel