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  • Overall the DDR kinase domain has a

    2019-07-16

    Overall, the DDR1 kinase domain has a typical kinase domain structure and adequate sequence and/or structure similarity with other kinase domains, as shown in Fig. 2, which allow homology modeling of the active and inactive conformations. In addition to conformational changes to the activation loop, αC-helix position and orientation of catalytic residues, conserved spatial arrangement patterns of residues have been identified in the active kinase conformation. Four residues in the ATP-binding site link together N and C lobes of the kinase domain 22, 23. Residues His764, Phe785, Met676, and Leu687 [Tyr164, Phe185, Leu95, and Leu106; His361, Phe382, Met290, and Leu301] form the so-called ‘hydrophobic spine’. An intact conformation of the igf 1 antagonist spine is essential for maintaining the active state conformation of kinase domain, whereas disruption of the arrangement leads to inactive conformation. The hydrophobic spine supports the relative orientation of the two lobes as a hinge for interconversion of the open and closed conformations required for binding ATP and releasing ADP 23, 24. Fig. 1a and b illustrate the hydrophobic spines in inactive conformation of DDR1 (PDB: 3ZOS) and active DDR1 conformation (homology model), respectively.
    Targeting DDR1 for inhibition DDR1 inhibitors reported so far are ATP competitive inhibitors that bind to either the active (type-1 inhibitors) or inactive (type-2 inhibitors) conformations, preventing transfer of the terminal phosphate group of ATP to the protein substrate. Screening for inhibitory activity against a panel of kinases identified imatinib [25], nilotinib [26], dasatinib [26], and bafetinib [27] as DDR1 inhibitors (Fig. 3). Day et al. reported inhibition of DDR1 by imatinib, nilotinib, and dasatinib with IC50 values of 43±2.4nM, 3.7±1.2nM and 1.35±0.2nM, respectively [28]. However, these inhibitors are not selective, as they were originally designed to target Abl kinase. Sun et al. identified (3-(2-(3-(morpholinomethyl)phenyl)thieno [3,2-b]pyridin-7-ylamino) phenol (LCB 03-0110 in Fig. 3) as a potent inhibitor of both DDR1 and DDR2 along with several other tyrosine kinases [29]. Recently, Gao et al. identified a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides as potent DDR1 inhibitors, the most potent of which (7rh and 7rj in Fig. 3) have IC50 values of 6.8 and 7.0nM, respectively [30]. Kim et al. reported two inhibitors, DDR1-IN-1 and DDR1-IN-2 (Fig. 3), which exhibit an IC50 of 105nM and 47nM, respectively [31].
    DDR1–inhibitor complexes Dasatinib is a type-1 inhibitor that targets kinase domains in the active form and is characterized by an open conformation of the activation loop (see below). Type-1 inhibitors bind the ATP site by mimicking the interaction of the adenine ring with the ‘hinge’ residues of protein. Even though there is no co-crystal structure of the DDR1–dasatinib complex, it is expected that dasatinib will bind in the so-called ‘open conformation’ of the DDR1 kinase domain, which is characterized by a ‘DFG-in’ configuration of the conserved triad DFG at the beginning of activation loop (Fig. 1b). By contrast, imatinib and nilotinib are type-2 inhibitors that bind to and stabilize an inactive kinase form that is characterized by ‘DFG-out’ conformation (see below). The ‘DFG-out’ motif opens an additional cavity, a hydrophobic allosteric site that, in addition to the ATP binding pocket, is targeted by type-2 inhibitors (Fig. 1a).
    Concluding remarks and future perspectives The availability of experimental structures as well as high-quality homology models makes DDR1 amenable for the application of structure-based drug discovery methods. Flexible docking with ROSETTALIGAND into crystal structures would improve docking accuracy. In addition, as the number of known DDR1 inhibitors grows 25, 26, 27, 29, 30, 31, 38, ligand-based drug discovery methods, such as quantitative structure–activity relation (SAR) models, could be developed. The discovery of inhibitors of DDR1 kinase activity might be beneficial in several pathological conditions where DDR1 has been identified as a potential therapeutic target.