CSC - IT Center for Science Ltd., P.O. Box 405, Espoo, FI-02101, Finland +358 9 4572235 ; +358 9 4572302 ;
Expert Opin Drug Discov. 2010 Jan;5(1):5-20. doi: 10.1517/17460440903468680.
Deep structural and chemical understanding of the protein target and computational methods for detection of receptor-selective ligands are important for the early drug discovery in the steroid receptor field.
This review focuses on the use of currently available structural information of the androgen receptor (AR) and known AR ligands to make computational strategies for the discovery of AR ligands in order to offer new chemical platforms for drug development.
AR is a challenging target for drug discovery and modeling even if there is a wealth of experimental data available. First, only the active structure of AR is currently known, which hampers the design of AR antagonists. Second, the structural similarity between the ligand-binding sites of AR and its mutated forms and closely related steroid receptors (SRs) such as progesterone receptors presents challenges for the development of drugs with receptor-selective function.
Research indicates that a very small chemical change in the structure of a non-steroidal ligand can cause a complete change in its activity. One source of this effect arises from binding to similar binding sites in related SRs and other proteins in the signaling pathway. Currently, computational methods are not able to predict the subtle differences between AR ligand activities but modeling does offer the possibility of generating new lead structures that might have the desired properties.
深入了解蛋白质靶标结构和化学性质，以及用于检测受体选择性配体的计算方法，对于甾体受体领域的早期药物发现非常重要。
本篇综述重点介绍了目前雄激素受体 (AR) 的结构信息和已知的 AR 配体的使用，以制定发现 AR 配体的计算策略，从而为药物开发提供新的化学平台。
即使有大量的实验数据可用，AR 仍然是药物发现和建模的一个具有挑战性的靶点。首先，目前仅知道 AR 的活性结构，这阻碍了 AR 拮抗剂的设计。其次，AR 的配体结合位点与其突变形式以及密切相关的甾体受体（SRs），如孕激素受体之间的结构相似性，给具有受体选择性功能的药物开发带来了挑战。
研究表明，非甾体配体结构的微小化学变化可能导致其活性的完全改变。这种效应的一个来源是与相关 SRs 和信号通路中的其他蛋白质的类似结合位点结合。目前，计算方法还无法预测 AR 配体活性之间的细微差异，但建模确实提供了生成可能具有所需特性的新先导结构的可能性。
