Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays | |
Hou, Tingjun3,4; Li, Dan4; Chang, Shan1; Xu, Lei1; Sun, Huiyong4; Tang, Qin4; Pang, Jinping4; Fu, Weitao4; Duan, Mojie2; Zhou, Wenfang3,4 | |
刊名 | GENOMICS PROTEOMICS & BIOINFORMATICS |
2019-12-01 | |
卷号 | 16期号:6页码:416-427 |
关键词 | Androgen receptor AR ligand Virtual screening AR agonist AR antagonist |
ISSN号 | 1672-0229 |
DOI | 10.1016/j.gpb.2018.03.007 |
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 IC50 values of HBP1-51 and HBP1-58 are 3.96 mu M and 4.92 mu M, respectively, which are even lower than that of enzalutamide (Enz, IC50 = 13.87 mu M), 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 newly-identified 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. |
资助项目 | National Key R&D Program of China[2016YFA0501701] ; National Key R&D Program of China[2016YFA0202900] ; National Natural Science Foundation of China[21575128] ; National Natural Science Foundation of China[81773632] ; National Natural Science Foundation of China[81302679] |
WOS关键词 | PROSTATE-CANCER ; MOLECULAR-DYNAMICS ; GENE-EXPRESSION ; DRUG DISCOVERY ; IDENTIFICATION ; MODULATOR ; RESISTANCE ; ANTIANDROGEN ; ANTAGONISTS ; DEATH |
WOS研究方向 | Genetics & Heredity |
语种 | 英语 |
出版者 | ELSEVIER SCIENCE BV |
WOS记录号 | WOS:000460533000006 |
资助机构 | National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key R&D Program of China ; National Key R&D Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China |
内容类型 | 期刊论文 |
源URL | [http://ir.wipm.ac.cn/handle/112942/14124] |
专题 | 中国科学院武汉物理与数学研究所 |
通讯作者 | Hou, Tingjun; Li, Dan |
作者单位 | 1.Jiangsu Univ Technol, Sch Elect & Informat Engn, Inst Bioinformat & Med Engn, Changzhou 213001, Peoples R China 2.Chinese Acad Sci, Natl Ctr Magnet Resonance Wuhan, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan 430071, Hubei, Peoples R China 3.Zhejiang Univ, State Key Lab Comp Aided Design & Comp Graph CAD, Hangzhou 310058, Zhejiang, Peoples R China 4.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China |
推荐引用方式 GB/T 7714 | Hou, Tingjun,Li, Dan,Chang, Shan,et al. Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays[J]. GENOMICS PROTEOMICS & BIOINFORMATICS,2019,16(6):416-427. |
APA | Hou, Tingjun.,Li, Dan.,Chang, Shan.,Xu, Lei.,Sun, Huiyong.,...&Zhou, Wenfang.(2019).Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays.GENOMICS PROTEOMICS & BIOINFORMATICS,16(6),416-427. |
MLA | Hou, Tingjun,et al."Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays".GENOMICS PROTEOMICS & BIOINFORMATICS 16.6(2019):416-427. |
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