Pharmacophore modelling and virtual screening for identification of new Aurora-A kinase inhibitors.
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.
Deng
Xiao-Qiang
XQ
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
Wang
Hui-Yuan
HY
Zhao
Ying-Lan
YL
Xiang
Ming-Li
ML
Jiang
Pei-Du
PD
Cao
Zhi-Xing
ZX
Zheng
Yu-Zhu
YZ
Luo
Shi-Dong
SD
Yu
Luo-Ting
LT
Wei
Yu-Quan
YQ
Yang
Sheng-Yong
SY
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*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases