title: Pharmacophore modelling and virtual screening for identification of new Aurora-A kinase inhibitors.
abstract: Aurora-A has been identified as one of the most attractive targets for cancer therapy and a considerable number of Aurora-A inhibitors have been reported recently. In order to clarify the essential structure-activity relationship for the known Aurora-A inhibitors as well as identify new lead compounds against Aurora-A, 3D pharmacophore models were developed based on the known inhibitors. The best hypothesis, Hypo1, was used to screen molecular structural databases, including Specs and China Natural Products Database for potential lead compounds. The hit compounds were subsequently subjected to filtering by Lipinski's rules and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally, 39 compounds were purchased for further in vitro assay against several human tumour cell lines including A549, MCF-7, HepG2 and PC-3, in which Aurora-A is overexpressed. Two compounds show very low micromolar inhibition potency against some of these tumour cells. And they have been selected for further investigation.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Deng
authors.forename: Hui-Yuan
authors.initials: HY
authors.lastname: Wang
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
authors.forename: Ming-Li
authors.initials: ML
authors.lastname: Xiang
authors.forename: Pei-Du
authors.initials: PD
authors.lastname: Jiang
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Cao
authors.forename: Yu-Zhu
authors.initials: YZ
authors.lastname: Zheng
authors.forename: Shi-Dong
authors.initials: SD
authors.lastname: Luo
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases