title: Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents.
abstract: Microtubule cytoskeletons are involved in many essential functions throughout the life cycle of cells, including transport of materials into cells, cell movement, and proper progression of cell division. Small compounds that can bind at the colchicine site of tubulin have drawn great attention because these agents can suppress or inhibit microtubule dynamics and tubulin polymerization. To find novel tubulin polymerization inhibitors as anti-mitotic agents, we performed a virtual screening study of the colchicine binding site on tubulin. Novel tubulin inhibitors were identified and characterized by their inhibitory activities on tubulin polymerization in vitro. The structural basis for the interaction of novel inhibitors with tubulin was investigated by molecular modeling, and we have proposed binding models for these hit compounds with tubulin. The proposed docking models were very similar to the binding pattern of colchicine or podophyllotoxin with tubulin. These new hit compound derivatives exerted growth inhibitory effects on the HL60 cell lines tested and exhibited strong cell cycle arrest at G2/M phase. Furthermore, these compounds induced apoptosis after cell cycle arrest. In this study, we show that the validated derivatives of compound 11 could serve as potent lead compounds for designing novel anti-cancer agents that target microtubules.
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Park
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Seung Kee
authors.initials: SK
authors.lastname: Moon
authors.forename: Sung Sook
authors.initials: SS
authors.lastname: Lee
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.forename: Kyun-Hwan
authors.initials: KH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D054852:Small Molecule Libraries; D014404:Tubulin; D050257:Tubulin Modulators