Shao Guangfeng, Bao Jingxiao, Pan Xiaolin, He Xiao, Qi Yifei, Zhang John Z H
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
NYU-ECNU Center for Computational Chemistry at NYU, Shanghai, China.
Front Mol Biosci. 2021 Mar 12;8:646524. doi: 10.3389/fmolb.2021.646524. eCollection 2021.
Androgen receptor (AR) is an important therapeutic target for the treatment of diseases such as prostate cancer, hypogonadism, muscle wasting, etc. In this study, the complex structures of the AR ligand-binding domain (LBD) with fifteen ligands were analyzed by molecular dynamics simulations combined with the alanine-scanning-interaction-entropy method (ASIE). The quantitative free energy contributions of the pocket residues were obtained and hotspot residues are quantitatively identified. Our calculation shows that that these hotspot residues are predominantly hydrophobic and their interactions with binding ligands are mainly van der Waals interactions. The total binding free energies obtained by summing over binding contributions by individual residues are in good correlation with the experimental binding data. The current quantitative analysis of binding mechanism of AR to ligands provides important insight on the design of future inhibitors.
雄激素受体（AR）是治疗前列腺癌、性腺功能减退、肌肉萎缩等疾病的重要治疗靶点。在本研究中，通过分子动力学模拟结合丙氨酸扫描相互作用熵方法（ASIE）分析了AR配体结合结构域（LBD）与15种配体的复合物结构。获得了口袋残基的定量自由能贡献，并定量鉴定了热点残基。我们的计算表明，这些热点残基主要是疏水的，它们与结合配体的相互作用主要是范德华相互作用。通过对各个残基的结合贡献求和得到的总结合自由能与实验结合数据具有良好的相关性。目前对AR与配体结合机制的定量分析为未来抑制剂的设计提供了重要的见解。
