title: A structure-based design of new C2- and C13-substituted taxanes: tubulin binding affinities and extended quantitative structure-activity relationships using comparative binding energy (COMBINE) analysis.
abstract: Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand-receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications.
authors.affiliation: Área de Farmacología, Departamento de Ciencias Biomédicas, Universidad de Alcalá, E-28871 Alcalá de Henares, Unidad Asociada al Instituto de Química Médica del CSIC, Madrid, Spain.
authors.forename: Claire
authors.initials: C
authors.lastname: Coderch
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Javier
authors.initials: J
authors.lastname: Klett
authors.forename: Shu-En
authors.initials: SE
authors.lastname: Zhang
authors.forename: Yun-Tao
authors.initials: YT
authors.lastname: Ma
authors.forename: Wang
authors.initials: W
authors.lastname: Shaorong
authors.forename: Ruth
authors.initials: R
authors.lastname: Matesanz
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.forename: Angeles
authors.initials: A
authors.lastname: Canales
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Wei-Shuo
authors.initials: WS
authors.lastname: Fang
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D043823:Taxoids; D014404:Tubulin