Sengupta Sindhuja, Maji Lalmohan, Das Pronoy Kanti, Teli Ghanshyam, Nag Mrinmoy, Khan Nirmalya, Haque Mridul, Matada Gurubasavaraja Swamy Purawarga
Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
NEF College of Pharmaceutical Education & Research, Nagaon, 782001, India.
Mol Divers. 2025 Jan 30. doi: 10.1007/s11030-024-11091-5.
Discoidin domain receptors (DDR) are categorized under tyrosine kinase receptors (RTKs) and play a crucial role in various etiological conditions such as cancer, fibrosis, atherosclerosis, osteoarthritis, and inflammatory diseases. The structural domain rearrangement of DDR1 and DDR2 involved six domains of interest namely N-terminal DS, DS-like, intracellular juxtamembrane, transmembrane juxtamembrane, extracellular juxtamembrane intracellular kinase domain, and the tail portion contains small C-tail linkage. DDR has not been explored to a wide extent to be declared as a prime target for any particular pathological condition. Very few scientific data are available so there is a need to study the receptors and their inhibitors. Still, there did not exist FDA-approved small molecules targeting DDR1 and DDR2 receptors so there is an urgent need to develop potent small molecules. Further, the structural features and ligand specificities encourage the researchers to be fascinated about the DDR and explore them for the mentioned biological conditions. Therefore, in the last few years, researchers have been involved in investigating the potent DDR inhibitors. The current review provides an outlook on the anatomy and physiology of DDR, focusing on the structural features of DDR receptors and the mechanism of signaling pathways. We have also compiled the evolutionary development status of DDR inhibitors according to their chemical classes, biological activity, selectivity, and structure-activity relationship. From biological activity analysis, it was revealed that compounds 64a (selectivity: DDR1) and 103a (selectivity: DDR2) were the most potent candidates with excellent activity with IC values of 4.67 and 3.2 nM, respectively.
盘状结构域受体（DDR）属于酪氨酸激酶受体（RTK），在多种病因相关病症中发挥关键作用，如癌症、纤维化、动脉粥样硬化、骨关节炎和炎症性疾病。DDR1和DDR2的结构域重排涉及六个感兴趣的结构域，即N端盘状结构域（DS）、类DS结构域、细胞内近膜结构域、跨膜近膜结构域、细胞外近膜细胞内激酶结构域，尾部包含小的C尾连接区。DDR尚未得到广泛研究，无法被宣布为任何特定病理状况的主要靶点。可用的科学数据非常少，因此有必要研究这些受体及其抑制剂。尽管如此，目前尚无美国食品药品监督管理局（FDA）批准的针对DDR1和DDR2受体的小分子药物，因此迫切需要开发有效的小分子药物。此外，其结构特征和配体特异性促使研究人员对DDR产生兴趣，并针对上述生物学状况进行探索。因此，在过去几年中，研究人员一直致力于研究有效的DDR抑制剂。本综述概述了DDR的解剖学和生理学，重点关注DDR受体的结构特征和信号通路机制。我们还根据DDR抑制剂的化学类别、生物活性、选择性和构效关系，汇编了其进化发展状况。从生物活性分析来看，化合物64a（选择性：DDR1）和103a（选择性：DDR2）是最有效的候选药物，活性优异，IC值分别为4.67和3.2 nM。
