6-氮杂甾醇类Ⅱ型5-α还原酶抑制剂的三维定量构效关系研究和虚拟筛选

3D-QSAR and virtual screening of 5α-reductase Ⅱ inhibitors of 6-azasteroids

摘要:

采用Topomer CoMFA对37个6-氮杂甾醇类抑制剂进行三维定量构效关系分析，新建模型的交互验证和拟合相关系数为q2=0.774，r2=0.965，结果表明模型具有良好的可信度和预测能力. 将基于配体的Topomer search虚拟筛选、基于受体的分子对接虚拟筛选和基于3D-QSAR模型的分子活性预测等方法运用到新抑制剂的分级筛选，最终获得4个高活性的新抑制剂分子. 新抑制剂的Surflex-dock结果显示6-氮杂甾醇类抑制剂与5AR-Ⅱ靶点的作用模式主要是氢键作用. MTT法生物学活性测试结果显示新抑制剂能显著抑制BPH-1细胞增殖，且抑制程度呈浓度依赖性. 通过分子对接机理解释和细胞学实验的抑制前列腺增生活性测试，这两种研究方式相互验证，证明此虚拟筛选方法能够为治疗良性前列腺增生的新药设计提供有效候选化合物.

Abstract:

Three-dimensional quantitative structure-activity relationship analysis of 37 6-azasteroids inhibitors was carried out by Topomer CoMFA. The new model’s cross validation and correlation coefficient were q2=0.774 and r2=0.965, respectively. The results show that the model has good prediction ability and reliability. Virtual screening based on Topomer search of ligand,virtual screening based on molecular docking of receptor and molecular activity prediction of 3D-QSAR model were applied to the new inhibitor grading screening. Finally, four new inhibitor compounds with high activity were obtained. The Surflex-dock results of new inhibitors showed that the interaction pattern between 6-azosterol inhibitors and 5α-reductaseⅡ target is mainly hydrogen bonding. The results of MTT assay showed that the new inhibitor could significantly inhibit the proliferation of BPH-1 cells and the degree of inhibition is concentration dependent. Molecular docking mechanism interpretation and prostatic growth inhibition assay in cytological experiments are mutually validated. It is proved that this virtual screening method can provide effective candidate compounds for the treatment of benign prostatic hyperplasia.