title: Generation of ligand-based pharmacophore model and virtual screening for identification of novel tubulin inhibitors with potent anticancer activity.
abstract: A pharmacophore model, Hypo1, was built on the basis of 21 training-set indole compounds with varying levels of antiproliferative activity. Hypo1 possessed important chemical features required for the inhibitors and demonstrated good predictive ability for biological activity, with high correlation coefficients of 0.96 and 0.89 for the training-set and test-set compounds, respectively. Further utilization of the Hypo1 pharmacophore model to screen chemical database in silico led to the identification of four compounds with antiproliferative activity. Among these four compounds, 43 showed potent antiproliferative activity against various cancer cell lines with the strongest inhibition on the proliferation of KB cells (IC(50) = 187 nM). Further biological characterization revealed that 43 effectively inhibited tubulin polymerization and significantly induced cell cycle arrest in G(2)-M phase. In addition, 43 also showed the in vivo-like anticancer effects. To our knowledge, 43 is the most potent antiproliferative compound with antitubulin activity discovered by computer-aided drug design. The chemical novelty of 43 and its anticancer activities make this compound worthy of further lead optimization.
authors.affiliation: Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China.
authors.forename: Yi-Kun
authors.initials: YK
authors.lastname: Chiang
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Wu
authors.forename: Chung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Chi-Yen
authors.initials: CY
authors.lastname: Chang
authors.forename: Huan-Yi
authors.initials: HY
authors.lastname: Jseng
authors.forename: Ming-Hsine
authors.initials: MH
authors.lastname: Wu
authors.forename: Jiun-Shyang
authors.initials: JS
authors.lastname: Leou
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Ping-Chiang
authors.initials: PC
authors.lastname: Lyu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001185:Artificial Intelligence; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D003365:Costs and Cost Analysis; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007624:KB Cells; D008024:Ligands; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D015203:Reproducibility of Results; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine