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

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.

Keywords: DDR1 and DDR2; Molecular docking studies; Selectivity; Structure–activity relationship; Synthetic pathways.