Loading...
Please wait, while we are loading the content...
Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays
| Content Provider | Scilit |
|---|---|
| Author | Zhou, Wenfang Duan, Mojie Fu, Weitao Pang, Jinping Tang, Qin Sun, Huiyong Xu, Lei Chang, Shan Li, Dan Hou, Tingjun |
| Copyright Year | 2018 |
| Description | Journal: Genomics, proteomics & bioinformatics 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 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, $IC_{50}$ = 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411960/pdf |
| Ending Page | 427 |
| Page Count | 12 |
| Starting Page | 416 |
| ISSN | 16720229 |
| e-ISSN | 22103244 |
| DOI | 10.1016/j.gpb.2018.03.007 |
| Journal | Genomics, proteomics & bioinformatics |
| Issue Number | 6 |
| Volume Number | 16 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2018-12-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Genomics, proteomics & bioinformatics Medicinal Chemistry Androgen Receptor Ar Ligand Virtual Screening Ar Agonist Ar Antagonist |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Medicine Molecular Biology Biochemistry Computational Mathematics |
