Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 19; pp. 7092 - 7100
• Main Authors: Kim, Nam Doo, Park, Eun-Sook, Kim, Young Hoon, Moon, Seung Kee, Lee, Sung Sook, Ahn, Soon Kil, Yu, Dae-Yeul, No, Kyoung Tai, Kim, Kyun-Hwan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2010; Elsevier
• Subjects: Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Cell Division - drug effects; Cell Proliferation - drug effects; Colchicine; Crystallography, X-Ray; Drug Discovery; Drug Screening Assays, Antitumor; G2 Phase - drug effects; General aspects; Humans; Medical sciences; Microtubule; Mitosis - drug effects; Models, Molecular; Molecular docking; Molecular Structure; Pharmacology. Drug treatments; Pharmacophore; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tumor Cells, Cultured; Virtual screening; Virtual screening; Microtubule; Colchicine; Pharmacophore; Molecular docking; Antineoplastic agent; Human; Promyelocytic leukemia; Antitubulin; Modeling; HL60 cell line; Cell line; Structure activity relation; Cell death; Chemical compound library; Molecular model; Binding mode; G2 Phase; Antimitotic; Tumor cell; Apoptosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.07.072

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.