Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays.
10.1016/j.gpb.2018.03.007
- Author:
Wenfang ZHOU
1
,
2
;
Mojie DUAN
3
;
Weitao FU
4
;
Jinping PANG
4
;
Qin TANG
4
;
Huiyong SUN
4
;
Lei XU
5
;
Shan CHANG
5
;
Dan LI
6
;
Tingjun HOU
1
,
7
Author Information
1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2. State Key Laboratory of Computer Aided Design and Computer Graphics (CAD&GC), Zhejiang University, Hangzhou 310058, China.
3. State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
4. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
5. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China.
6. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: lidancps@zju.edu.cn.
7. State Key Laboratory of Computer Aided Design and Computer Graphics (CAD&GC), Zhejiang University, Hangzhou 310058, China. Electronic address: tingjunhou@zju.edu.cn.
- Publication Type:Journal Article
- Keywords:
AR agonist;
AR antagonist;
AR ligand;
Androgen receptor;
Virtual screening
- MeSH:
Androgen Receptor Antagonists;
pharmacology;
Androgens;
metabolism;
pharmacology;
Biological Assay;
Cell Line, Tumor;
Drug Discovery;
methods;
Humans;
Ligands;
Male;
Molecular Docking Simulation;
Molecular Dynamics Simulation;
Phenylthiohydantoin;
analogs & derivatives;
pharmacology;
Principal Component Analysis;
Prostatic Neoplasms;
drug therapy;
Protein Binding;
physiology;
Protein Conformation;
drug effects;
Receptors, Androgen;
metabolism
- From:
Genomics, Proteomics & Bioinformatics
2018;16(6):416-427
- CountryChina
- Language:English
-
Abstract:
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 values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC = 13.87 µM), 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.
