discoveryofnovelandrogenreceptorligandsbystructurebasedvirtualscreeningandbioassays

	discoveryofnovelandrogenreceptorligandsbystructurebasedvirtualscreeningandbioassays
	Zhou Wenfang 2; Duan Mojie 1; Fu Weitao 2; Pang Jinping 2; Tang Qin 2; Sun Huiyong 2; Xu Lei 3; Chang Shan 3; Li Dan 2; Hou Tingjun 2
刊名	genomicsproteomicsbioinformatics
	2018
卷号	16 期号:6 页码:416
ISSN号	1672-0229
英文摘要	Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC_(50) values of HBP1-51 and HBP1-58 are 3.96 mM and 4.92 mM, respectively, which are even lower than that of enzalutamide (Enz, IC_(50) = 13.87 mM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
语种	英语
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/15752]
专题	中国科学院武汉物理与数学研究所
作者单位	1.中国科学院武汉物理与数学研究所 2.浙江大学 3.江苏理工学院
推荐引用方式 GB/T 7714	Zhou Wenfang,Duan Mojie,Fu Weitao,et al. discoveryofnovelandrogenreceptorligandsbystructurebasedvirtualscreeningandbioassays[J]. genomicsproteomicsbioinformatics,2018,16(6):416.
APA	Zhou Wenfang.,Duan Mojie.,Fu Weitao.,Pang Jinping.,Tang Qin.,...&Hou Tingjun.(2018).discoveryofnovelandrogenreceptorligandsbystructurebasedvirtualscreeningandbioassays.genomicsproteomicsbioinformatics,16(6),416.
MLA	Zhou Wenfang,et al."discoveryofnovelandrogenreceptorligandsbystructurebasedvirtualscreeningandbioassays".genomicsproteomicsbioinformatics 16.6(2018):416.