title: Discovery of novel tubulin inhibitors via structure-based hierarchical virtual screening.
abstract: To discover novel tubulin inhibitors, we performed structure-based virtual screening against the colchicine binding pocket. In combination with a hierarchical docking and scoring procedure, the structural information of an additional subpocket in colchicine site was applied to filter out the undesired docking hits. This strategy automatically resulted in 63 candidates meeting the structural and energetic criteria from a screening library containing approximately 100,000 diverse druglike compounds. Among them, nine molecules were chosen for experimental validation, which all share the similar binding pose and contain an enriched scaffold bearing thiophene core. Encouragingly, five compounds are active in tubulin polymerization assay. The most potent inhibitor, 2-(2-fluorobenzamido)-3-carboxamide-4,5-dimethylthiophene, is structurally distinct to any known colchicine site binders and has higher ligand efficiency than colchicine. On the basis of its predicted binding pose, we systematically probed its binding characteristics by testing series of structural modifications. The obtained structure-activity relationship results are consistent with our binding model, and the inhibition activities of two analogues are improved by 2-fold. We expect that the novel structure discovered in the present study may serve as a starting point for developing tubulin inhibitors with improved efficacy and fewer side effects. We also expect that our hierarchical strategy may be generally applicable in structure-based virtual screening campaigns.
authors.affiliation: School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Cao
authors.forename: Minyu
authors.initials: M
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Yin
authors.forename: Quanhai
authors.initials: Q
authors.lastname: Liu
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wang
authors.forename: Niu
authors.initials: N
authors.lastname: Huang
mesh_terms: D000465:Algorithms; D001549:Benzamides / Q000737:chemistry*; D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D058105:Polymerization; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013876:Thiophenes / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000737:chemistry*; D014584:User-Computer Interface
chemical_list: C579247:2-(2-fluorobenzamido)-3-carboxamide-4,5-dimethylthiophene; D001549:Benzamides; D008024:Ligands; D054852:Small Molecule Libraries; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine