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.
雄激素受体（AR）是配体依赖的转录因子，在前列腺癌、肌肉萎缩和骨质疏松等重大疾病的发生和发展中扮演重要角色。被配体激活后，AR的构型发生变化，募集共激活剂，引起AR信号通路下游的一系列反应。因此，AR配体对于这些疾病的治疗具有极高的潜在价值。该研究基于AR与其激动剂的复合物晶体结构，通过以对接为主要手段的虚拟筛选寻找AR的新型配体。58个结构各异的化合物被筛选出来。其中HBP1-3，HBP1-17，HBP1-38，HBP1-51和HBP1-58等5个化合物在竞争性结合实验中展现出对AR配体结合域的很强的结合能力。HBP1-51和HBP1-58的IC50值分别为3.96 μM和4.92 μM，低于已上市的第二代AR拮抗剂比卡鲁胺（IC50 = 13.87 μM）。进一步的生物实验证明：HBP1-51是AR激动剂，而HBP1-58是AR拮抗剂。此外，该研究进行了分子动力学模拟（MD）和主成分分析（PCA），揭示了这些新型小分子配体与AR的结合原理。建立的模型结构显示，当与激动剂和拮抗剂结合时，AR的H12构型变化明显不同。该研究提供了一条高效筛选AR配体的途径，同时为治疗AR相关疾病的新型药物的开发提供了素材。





PDF全文下载地址:

http://gpb.big.ac.cn/articles/download/677