title: Computational approach to the identification of novel Aurora-A inhibitors.
abstract: Aurora kinase A has been emerging as a key therapeutic target for the design of anticancer drugs. For the purpose of finding biologically active and novel compounds and providing new ideas for drug-design, we performed virtual screening using commercially available databases. A three-dimensional common feature pharmacophore model was developed with the HipHop program provided in the Catalyst software package, and this model was used as a query for screening the databases. A recursive partitioning (RP) model was developed as a filtering system, which was able to classify active and inactive compounds. Eventually, a step-wise virtual screening procedure was conducted by applying the common feature pharmacophore and the RP model in succession to discover novel potent Aurora-A inhibitors. A total of 68 compounds were selected for testing of their in vitro anticancer activities against various human cancer cell lines. Based on the activity data, we have identified fifteen compounds that warrant further investigation. Several compounds have a high inhibition rate (above 80% at 10 μM) and a GI₅₀ lower than 5 μM for the cell lines DU145 and HT29. Enzyme assay for these compounds identified hits with micro molar activity. Compound C11 has the highest activity (IC₅₀ = 5.09 μM). The hits obtained from this screening scheme could be potential drug candidates after further optimization.
authors.affiliation: Neuro-Medicine Center, Korea Institute of Science and Technology, Cheongryang, Seoul, Republic of Korea.
authors.forename: Mohammad Neaz
authors.initials: MN
authors.lastname: Morshed
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.forename: Ki-Cheol
authors.initials: KC
authors.lastname: Han
authors.forename: Eun Gyeong
authors.initials: EG
authors.lastname: Yang
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases