Explanatory review on DDR inhibitors: their biological activity, synthetic route, and structure-activity relationship.

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Sindhuja Sengupta, Lalmohan Maji, Pronoy Kanti Das, Ghanshyam Teli, Mrinmoy Nag, Nirmalya Khan, Mridul Haque, Gurubasavaraja Swamy Purawarga Matada
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引用次数: 0

Abstract

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 IC50 values of 4.67 and 3.2 nM, respectively.

DDR抑制剂的生物活性、合成途径及构效关系的研究进展。
盘状蛋白结构域受体(DDR)属于酪氨酸激酶受体(RTKs),在各种病因如癌症、纤维化、动脉粥样硬化、骨关节炎和炎症性疾病中起着至关重要的作用。DDR1和DDR2的结构域重排涉及6个感兴趣的结构域,即n端DS、DS样、细胞内近膜、跨膜近膜、细胞外近膜胞内激酶结构域,尾部含有小的c尾连锁。DDR尚未被广泛地探讨,以宣布为任何特定病理状况的主要目标。科学数据很少,因此有必要对受体及其抑制剂进行研究。然而,目前还没有fda批准的靶向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,结构特征和配体特异性鼓励研究人员对DDR着迷,并为上述生物条件探索它们。因此,在过去的几年里,研究人员一直在研究有效的DDR抑制剂。本文综述了DDR的解剖学和生理学研究进展,重点介绍了DDR受体的结构特征和信号通路的机制。我们还根据DDR抑制剂的化学分类、生物活性、选择性和构效关系,整理了它们的进化发展状况。生物活性分析表明,化合物64a(选择性:DDR1)和化合物103a(选择性:DDR2)具有较好的活性,IC50值分别为4.67和3.2 nM。
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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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