Use of the tubulin bound paclitaxel conformation for structure-based rational drug design.
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.
Geney
Raphaël
R
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York, 11794, USA.
Sun
Liang
L
Pera
Paula
P
Bernacki
Ralph J
RJ
Xia
Shujun
S
Horwitz
Susan B
SB
Simmerling
Carlos L
CL
Ojima
Iwao
I
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*
D014404:Tubulin; D017239:Paclitaxel