CORC  > 武汉物理与数学研究所  > 中国科学院武汉物理与数学研究所
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
SourceGenomics proteomics & bioinformatics
2019-12-01
Volume16Issue:6Pages:416-427
KeywordAndrogen receptor Ar ligand Virtual screening Ar agonist Ar antagonist
ISSN1672-0229
DOI10.1016/j.gpb.2018.03.007
English AbstractAndrogen 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.
Funding ProjectNational 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 KeywordPROSTATE-CANCER ; MOLECULAR-DYNAMICS ; GENE-EXPRESSION ; DRUG DISCOVERY ; IDENTIFICATION ; MODULATOR ; RESISTANCE ; ANTIANDROGEN ; ANTAGONISTS ; DEATH
WOS Research AreaGenetics & Heredity
Language英语
WOS IDWos:000460533000006
PublisherELSEVIER SCIENCE BV
Funding OrganizationNational 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
Citation statistics
Content Type期刊论文
URIhttp://www.corc.org.cn/handle/1471x/2538923
Collection中国科学院武汉物理与数学研究所
Corresponding AuthorHou, tingjun; Li, dan
Affiliation1.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
Recommended Citation
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.
Files in This Item:
There are no files associated with this item.
Related Services
Usage statistics
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.

 

©版权所有 ©2017 CSpace - Powered by CSpace