title: Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin.
abstract: Although the structure has been elucidated for the binding of colchicine and podophyllotoxin as potent destabilizer for microtubule formation, very little is known about MDL-27048, a competitive inhibitor for colchicine and podophyllotoxin. The structural basis for the interaction of antimitotic agents with tubulin was investigated by molecular modeling, and we propose binding models for MDL-27048 against tubulin. The proposed model was not only consistent with previous competition experiment data between colchicine and MDL-27048, but further suggested an additional binding cavity on tubulin. Based on this finding from the proposed MDL-tubulin complex, we performed molecular design studies to identify new antimitotic agents. These new chalcone derivatives exerted growth inhibitory effects on all four human hepatoma and one renal epithelial cell lines tested and induced strong cell cycle arrest at G2/M phase. Furthermore, these compounds exhibited a strong inhibitory effect on tubulin polymerization in vitro. Therefore, we suggest that the validated MDL-27048 model would serve as a potent platform for designing new molecular entities for anticancer agents targeted to microtubules.
authors.affiliation: Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749, Korea.
authors.forename: Do Yoon
authors.initials: DY
authors.lastname: Kim
authors.forename: Kyun-Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Cheol Kyu
authors.initials: CK
authors.lastname: Han
authors.forename: Jeong Hyeok
authors.initials: JH
authors.lastname: Yoon
authors.forename: Seung Kee
authors.initials: SK
authors.lastname: Moon
authors.forename: Sung Sook
authors.initials: SS
authors.lastname: Lee
authors.forename: Baik L
authors.initials: BL
authors.lastname: Seong
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003078:Colchicine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011034:Podophyllotoxin / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D014404:Tubulin; D050257:Tubulin Modulators; C062014:MDL 27048; D002599:Chalcone; D011034:Podophyllotoxin; D003078:Colchicine