Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Den Dolech 2, 5612AZ, Eindhoven, the Netherlands.
Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Den Dolech 2, 5612AZ, Eindhoven, the Netherlands.
Mol Cell Endocrinol. 2019 Apr 5;485:20-34. doi: 10.1016/j.mce.2019.01.022. Epub 2019 Jan 28.
Nuclear Receptors (NRs) are multi-domain proteins, whose natural regulation occurs via ligands for a classical, orthosteric, binding pocket and via intra- and inter-domain allosteric mechanisms. Allosteric modulation of NRs via synthetic small molecules has recently emerged as an interesting entry to address the need for small molecules targeting NRs in pathology, via novel modes of action and with beneficial profiles. In this review the general concept of allosteric modulation in drug discovery is first discussed, serving as a background and inspiration for NRs. Subsequently, the review focuses on examples of small molecules that allosterically modulate NRs, with a strong focus on structural information and the ligand binding domain. Recently discovered nanomolar potent allosteric site NR modulators are catapulting allosteric targeting of NRs to the center of attention. The obtained insights serve as a basis for recommendations for the next steps to take in allosteric small molecular targeting of NRs.
核受体（NRs）是多结构域蛋白，其天然调节通过经典的、正位的配体结合口袋中的配体以及通过域内和域间变构机制发生。通过合成小分子对 NRs 的变构调节最近作为一种有趣的方法出现，通过新的作用模式和有益的特征来满足针对病理学中 NRs 的小分子的需求。在这篇综述中，首先讨论了药物发现中变构调节的一般概念，作为 NRs 的背景和灵感。随后，综述重点介绍了变构调节 NRs 的小分子的例子，重点关注结构信息和配体结合域。最近发现的具有纳米摩尔效力的强效变构 NR 调节剂正在将 NRs 的变构靶向推向关注的中心。获得的见解为变构小分子靶向 NR 的下一步提供了依据。
