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 IC50 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, IC50 = 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.
Highlights
Androgen receptor (AR) is a member of the steroid hormone nuclear receptor (NR) superfamily [1]
Crystal structures of AR-ligand binding domain (LBD) in complex with agonists may serve as the good starting points for the screening of agonists and SARMs
We have applied a structure-based virtual screening (VS) to search for novel AR ligands and identified 58 compounds for bioassay validation
Summary
Androgen receptor (AR) is a member of the steroid hormone nuclear receptor (NR) superfamily [1]. AR is involved in a number of severe diseases, such as prostate cancer (PCa) [2], muscle atrophy [3], and osteoporosis [4]. PCa is a widespread disease in men and is one of the leading causes for cancer death worldwide. It has been reported that AR gene and protein are both generally overexpressed at late stage of PCa [5,6]. AR overexpression augments the response of AR signaling pathway to residual androgens, and is one of the main driving forces for the progression into the lethal castration-resistant PCa [5,6]. AR antagonists such as the well-known flutamide and bicalutamide (Bic) have been successfully used to treat PCa for years [2]
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