title: Use of the tubulin bound paclitaxel conformation for structure-based rational drug design.
abstract: A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.
authors.affiliation: Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York, 11794, USA.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Geney
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Paula
authors.initials: P
authors.lastname: Pera
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: Shujun
authors.initials: S
authors.lastname: Xia
authors.forename: Susan B
authors.initials: SB
authors.lastname: Horwitz
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Simmerling
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D014404:Tubulin; D017239:Paclitaxel