Target Information
| Target General Information | Top | |||||
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| Target ID |
T09185
(Former ID: TTDI03158)
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| Target Name |
Epithelial discoidin domain receptor 1 (DDR1)
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| Synonyms |
Tyrosine-protein kinase CAK; Tyrosine kinase DDR; TRKE; TRK E; RTK6; Protein-tyrosine kinase RTK-6; Protein-tyrosine kinase 3A; PTK3A; NTRK4; NEP; Mammary carcinoma kinase 10; MCK-10; HGK2; Epithelial discoidin domain-containing receptor 1; EDDR1; Discoidin receptor tyrosine kinase; Cell adhesion kinase; CD167a; CD167 antigen-like family member A
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| Gene Name |
DDR1
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing. Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11. Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| Sequence |
MGPEALSSLLLLLLVASGDADMKGHFDPAKCRYALGMQDRTIPDSDISASSSWSDSTAAR
HSRLESSDGDGAWCPAGSVFPKEEEYLQVDLQRLHLVALVGTQGRHAGGLGKEFSRSYRL RYSRDGRRWMGWKDRWGQEVISGNEDPEGVVLKDLGPPMVARLVRFYPRADRVMSVCLRV ELYGCLWRDGLLSYTAPVGQTMYLSEAVYLNDSTYDGHTVGGLQYGGLGQLADGVVGLDD FRKSQELRVWPGYDYVGWSNHSFSSGYVEMEFEFDRLRAFQAMQVHCNNMHTLGARLPGG VECRFRRGPAMAWEGEPMRHNLGGNLGDPRARAVSVPLGGRVARFLQCRFLFAGPWLLFS EISFISDVVNNSSPALGGTFPPAPWWPPGPPPTNFSSLELEPRGQQPVAKAEGSPTAILI GCLVAIILLLLLIIALMLWRLHWRRLLSKAERRVLEEELTVHLSVPGDTILINNRPGPRE PPPYQEPRPRGNPPHSAPCVPNGSALLLSNPAYRLLLATYARPPRGPGPPTPAWAKPTNT QAYSGDYMEPEKPGAPLLPPPPQNSVPHYAEADIVTLQGVTGGNTYAVPALPPGAVGDGP PRVDFPRSRLRFKEKLGEGQFGEVHLCEVDSPQDLVSLDFPLNVRKGHPLLVAVKILRPD ATKNARNDFLKEVKIMSRLKDPNIIRLLGVCVQDDPLCMITDYMENGDLNQFLSAHQLED KAAEGAPGDGQAAQGPTISYPMLLHVAAQIASGMRYLATLNFVHRDLATRNCLVGENFTI KIADFGMSRNLYAGDYYRVQGRAVLPIRWMAWECILMGKFTTASDVWAFGVTLWEVLMLC RAQPFGQLTDEQVIENAGEFFRDQGRQVYLSRPPACPQGLYELMLRCWSRESEQRPPFSQ LHRFLAEDALNTV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Dasatinib | Ligand Info | |||||
| Structure Description | Fragment-based discovery of potent and selective DDR1/2 inhibitors | PDB:5BVW | ||||
| Method | X-ray diffraction | Resolution | 1.94 Å | Mutation | No | [6] |
| PDB Sequence |
DFPRSRLRFK
613 EKLGEGQFGE623 VHLCEVDSHP649 LLVAVKILRP659 DATKNARNDF669 LKEVKIMSRL 679 KDPNIIRLLG689 VCVQDDPLCM699 ITDYMENGDL709 NQFLSAHQLE719 DKPTISYPML 743 LHVAAQIASG753 MRYLATLNFV763 HRDLATRNCL773 VGENFTIKIA783 DFGLYAGDYY 797 RVQGRAVLPI807 RWMAWECILM817 GKFTTASDVW827 AFGVTLWEVL837 MLCRAQPFGQ 847 LTDEQVIENA857 GEFFRDQGRQ867 VYLSRPPACP877 QGLYELMLRC887 WSRESEQRPP 897 FSQLHRFLAE907 DALN
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LEU616
3.611
GLY617
4.951
VAL624
3.733
ALA653
3.336
VAL654
3.984
LYS655
3.545
GLU672
3.708
MET676
3.565
ILE685
3.923
MET699
3.851
ILE700
4.762
THR701
3.086
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Imatinib | Ligand Info | |||||
| Structure Description | Crystal structure of the human DDR1 kinase domain in complex with imatinib | PDB:4BKJ | ||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [7] |
| PDB Sequence |
MPRVDFPRSR
609 LRFKEKLGEG619 QFGEVHLCEV629 DSPQDLVSLD639 FPLNVRKGHP649 LLVAVKILRP 659 DATKNARNDF669 LKEVKIMSRL679 KDPNIIRLLG689 VCVQDDPLCM699 ITDYMENGDL 709 NQFLSAHQLE719 DPTISYPMLL744 HVAAQIASGM754 RYLATLNFVH764 RDLATRNCLV 774 GENFTIKIAD784 FGMSRNLYAG794 DYYRAVLPIR808 WMAWECILMG818 KFTTASDVWA 828 FGVTLWEVLM838 LCRAQPFGQL848 TDEQVIENAG858 EFFRDQGRQV868 YLSRPPACPQ 878 GLYELMLRCW888 SRESEQRPPF898 SQLHRFLAED908 ALNTV
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LEU616
4.446
VAL624
3.614
ALA653
3.469
VAL654
3.953
LYS655
3.485
GLU672
2.918
ILE675
3.844
MET676
3.487
LEU679
3.922
ILE685
3.445
MET699
3.756
ILE700
4.744
THR701
2.860
ASP702
4.014
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Similarity Proteins
Human Tissue Distribution
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| References | Top | |||||
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| REF 1 | Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem. 2013 Apr 25;56(8):3281-95. | |||||
| REF 2 | Quinazolinedione derivative. US9567304. | |||||
| REF 3 | Fused 2-aminothiazole compounds. US8765747. | |||||
| REF 4 | Thieno[3,2-D]pyrimidine derivatives having inhibitory activity for protein kinases. US9156852. | |||||
| REF 5 | Benzamide derivative. US9695118. | |||||
| REF 6 | Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. ACS Med Chem Lett. 2015 Jun 4;6(7):798-803. | |||||
| REF 7 | Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. J Mol Biol. 2014 Jun 26;426(13):2457-70. | |||||
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