title: Combined Molecular Docking, 3D-QSAR, and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine-binding Site.
abstract: Interference with dynamic equilibrium of microtubule-tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure-activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine-site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D-QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A-132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs.
authors.affiliation: College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210073, China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
authors.affiliation: College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210073, China.
authors.forename: Lin-Guo
authors.initials: LG
authors.lastname: Zhao
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003078:Colchicine / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D050257:Tubulin Modulators; D003078:Colchicine
keywords: 3D-QSAR; antitumor agents; colchicine-binding site; microtubules; pharmacophore