Target Information
| Target General Information | Top | |||||
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| Target ID |
T51282
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| Target Name |
Rho-associated protein kinase 1 (ROCK1)
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| Synonyms |
Rok; Rho-associated, coiled-coil containing protein kinase 1; Rho-associated kinase 1; Rho kinase; ROCK1; ROCK; P160ROCK; P160(rock); P160 ROCK-1; Let-502 kinase
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| Gene Name |
ROCK1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Glaucoma [ICD-11: 9C61] | |||||
| Function |
Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress. Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis. Plays a role in terminal erythroid differentiation. May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles. Promotes keratinocyte terminal differentiation. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| Sequence |
MSTGDSFETRFEKMDNLLRDPKSEVNSDCLLDGLDALVYDLDFPALRKNKNIDNFLSRYK
DTINKIRDLRMKAEDYEVVKVIGRGAFGEVQLVRHKSTRKVYAMKLLSKFEMIKRSDSAF FWEERDIMAFANSPWVVQLFYAFQDDRYLYMVMEYMPGGDLVNLMSNYDVPEKWARFYTA EVVLALDAIHSMGFIHRDVKPDNMLLDKSGHLKLADFGTCMKMNKEGMVRCDTAVGTPDY ISPEVLKSQGGDGYYGRECDWWSVGVFLYEMLVGDTPFYADSLVGTYSKIMNHKNSLTFP DDNDISKEAKNLICAFLTDREVRLGRNGVEEIKRHLFFKNDQWAWETLRDTVAPVVPDLS SDIDTSNFDDLEEDKGEEETFPIPKAFVGNQLPFVGFTYYSNRRYLSSANPNDNRTSSNA DKSLQESLQKTIYKLEEQLHNEMQLKDEMEQKCRTSNIKLDKIMKELDEEGNQRRNLEST VSQIEKEKMLLQHRINEYQRKAEQENEKRRNVENEVSTLKDQLEDLKKVSQNSQLANEKL SQLQKQLEEANDLLRTESDTAVRLRKSHTEMSKSISQLESLNRELQERNRILENSKSQTD KDYYQLQAILEAERRDRGHDSEMIGDLQARITSLQEEVKHLKHNLEKVEGERKEAQDMLN HSEKEKNNLEIDLNYKLKSLQQRLEQEVNEHKVTKARLTDKHQSIEEAKSVAMCEMEKKL KEEREAREKAENRVVQIEKQCSMLDVDLKQSQQKLEHLTGNKERMEDEVKNLTLQLEQES NKRLLLQNELKTQAFEADNLKGLEKQMKQEINTLLEAKRLLEFELAQLTKQYRGNEGQMR ELQDQLEAEQYFSTLYKTQVKELKEEIEEKNRENLKKIQELQNEKETLATQLDLAETKAE SEQLARGLLEEQYFELTQESKKAASRNRQEITDKDHTVSRLEEANSMLTKDIEILRRENE ELTEKMKKAEEEYKLEKEEEISNLKAAFEKNINTERTLKTQAVNKLAEIMNRKDFKIDRK KANTQDLRKKEKENRKLQLELNQEREKFNQMVVKHQKELNDMQAQLVEECAHRNELQMQL ASKESDIEQLRAKLLDLSDSTSVASFPSADETDGNLPESRIEGWLSVPNRGNIKRYGWKK QYVVVSSKKILFYNDEQDKEQSNPSMVLDIDKLFHVRPVTQGDVYRAETEEIPKIFQILY ANEGECRKDVEMEPVQQAEKTNFQNHKGHEFIPTLYHFPANCDACAKPLWHVFKPPPALE CRRCHVKCHRDHLDKKEDLICPCKVSYDVTSARDMLLLACSQDEQKKWVTHLVKKIPKNP PSGFVRASPRTLSTRSTANQSFRKVVKNTSGKTS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A03237 | |||||
| HIT2.0 ID | T60DK9 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Netarsudil | Drug Info | Approved | Open-angle glaucoma | [1] | |
| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | H-1152 | Drug Info | Phase 2 | Pulmonary arterial hypertension | [2] | |
| 2 | SAR-407899 | Drug Info | Phase 2 | Diabetic nephropathy | [3] | |
| 3 | INS-117548 | Drug Info | Phase 1 | Glaucoma/ocular hypertension | [4] | |
| 4 | GSK269962A | Drug Info | Clinical trial | Inflammation | [5] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | CDE-5110 | Drug Info | Terminated | Inflammation | [6] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 34 Inhibitor drugs | + | ||||
| 1 | Netarsudil | Drug Info | [1] | |||
| 2 | H-1152 | Drug Info | [7], [8] | |||
| 3 | SAR-407899 | Drug Info | [9] | |||
| 4 | GSK269962A | Drug Info | [5] | |||
| 5 | PMID28048944-Compound-19 | Drug Info | [11] | |||
| 6 | PMID28048944-Compound-2 | Drug Info | [11] | |||
| 7 | PMID28048944-Compound-20 | Drug Info | [11] | |||
| 8 | PMID28048944-Compound-21 | Drug Info | [11] | |||
| 9 | PMID28048944-Compound-3 | Drug Info | [11] | |||
| 10 | PMID28048944-Compound-4 | Drug Info | [11] | |||
| 11 | PMID28048944-Compound-5 | Drug Info | [11] | |||
| 12 | PMID28048944-Compound-6 | Drug Info | [11] | |||
| 13 | PMID28048944-Compound-7 | Drug Info | [11] | |||
| 14 | CDE-5110 | Drug Info | [12] | |||
| 15 | (4-Fluoro-phenyl)-(9H-purin-6-yl)-amine | Drug Info | [13] | |||
| 16 | 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole | Drug Info | [14] | |||
| 17 | Acid-activated omeprazole | Drug Info | [15] | |||
| 18 | AMA-237 | Drug Info | [16] | |||
| 19 | AS-1892802 | Drug Info | [16] | |||
| 20 | ATS-907 | Drug Info | [16] | |||
| 21 | Bisindolylmaleimide-I | Drug Info | [17] | |||
| 22 | CI-1040 | Drug Info | [17] | |||
| 23 | Fasudil | Drug Info | [18], [19] | |||
| 24 | KN-62 | Drug Info | [17] | |||
| 25 | KT-5720 | Drug Info | [17] | |||
| 26 | PMID19364658C33 | Drug Info | [20] | |||
| 27 | PMID20462760C22 | Drug Info | [21] | |||
| 28 | PMID20684608C35 | Drug Info | [22] | |||
| 29 | RKI-1447 | Drug Info | [23] | |||
| 30 | RO-316233 | Drug Info | [17] | |||
| 31 | Ro31-8220 | Drug Info | [17] | |||
| 32 | SB-747651A | Drug Info | [24] | |||
| 33 | SR-3850 | Drug Info | [16] | |||
| 34 | TRN-101 | Drug Info | [16] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | INS-117548 | Drug Info | [10] | |||
| 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: Ximelegatran | Ligand Info | |||||
| Structure Description | Crystal Structure of ROCK I bound to Y-27632 | PDB:2ETR | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [25] |
| PDB Sequence |
SFETRFEKMD
15 NLLRDPKSEV25 NSDCLLDGLD35 ALVYDLDFPA45 LRKNKNIDNF55 LSRYKDTINK 65 IRDLRMKAED75 YEVVKVIGRG85 AFGEVQLVRH95 KSTRKVYAMK105 LLSKFEMIKR 115 SDSAFFWEER125 DIMAFANSPW135 VVQLFYAFQD145 DRYLYMVMEY155 MPGGDLVNLM 165 SNYDVPEKWA175 RFYTAEVVLA185 LDAIHSMGFI195 HRDVKPDNML205 LDKSGHLKLA 215 DFGTCMKMNK225 EGMVRCDTAV235 GTPDYISPEV245 LKSQGGDGYY255 GRECDWWSVG 265 VFLYEMLVGD275 TPFYADSLVG285 TYSKIMNHKN295 SLTFPDDNDI305 SKEAKNLICA 315 FLTDREVRLG325 RNGVEEIKRH335 LFFKNDQWAW345 ETLRDTVAPV355 VPDLSSDIDT 365 SNFDDLEEDK375 GEEETFPIPK385 AFVGNQLPFV395 GFTYYSNRRY405 |
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| Ligand Name: H-1152 | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF ROCK I BOUND TO H-1152P A DI-METHYLATED VARIANT OF FASUDIL | PDB:3D9V | ||||
| Method | X-ray diffraction | Resolution | 3.30 Å | Mutation | No | [25] |
| PDB Sequence |
SFETRFEKMD
15 NLLRDPKSEV25 NSDCLLDGLD35 ALVYDLDFPA45 LRKNKNIDNF55 LSRYKDTINK 65 IRDLRMKAED75 YEVVKVIGRG85 AFGEVQLVRH95 KSTRKVYAMK105 LLSKFEMIKR 115 SDSAFFWEER125 DIMAFANSPW135 VVQLFYAFQD145 DRYLYMVMEY155 MPGGDLVNLM 165 SNYDVPEKWA175 RFYTAEVVLA185 LDAIHSMGFI195 HRDVKPDNML205 LDKSGHLKLA 215 DFGTCMKMNK225 EGMVRCDTAV235 GTPDYISPEV245 LKSQGGDGYY255 GRECDWWSVG 265 VFLYEMLVGD275 TPFYADSLVG285 TYSKIMNHKN295 SLTFPDDNDI305 SKEAKNLICA 315 FLTDREVRLG325 RNGVEEIKRH335 LFFKNDQWAW345 ETLRDTVAPV355 VPDLSSDIDT 365 SNFDDLEEDK375 GEEETFPIPK385 AFVGNQLPFV395 GFTYYSNRRY405 |
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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 Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| cGMP-PKG signaling pathway | hsa04022 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Chemokine signaling pathway | hsa04062 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Sphingolipid signaling pathway | hsa04071 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Vascular smooth muscle contraction | hsa04270 | Affiliated Target |
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| Class: Organismal Systems => Circulatory system | Pathway Hierarchy | ||
| TGF-beta signaling pathway | hsa04350 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Focal adhesion | hsa04510 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Tight junction | hsa04530 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Platelet activation | hsa04611 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Leukocyte transendothelial migration | hsa04670 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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| Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
| Oxytocin signaling pathway | hsa04921 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 20 | Degree centrality | 2.15E-03 | Betweenness centrality | 8.72E-04 |
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| Closeness centrality | 2.41E-01 | Radiality | 1.42E+01 | Clustering coefficient | 2.05E-01 |
| Neighborhood connectivity | 3.53E+01 | Topological coefficient | 7.46E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| 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 | ||||||
| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85. | |||||
| REF 2 | An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthalmol. 2014; 8: 883-890. | |||||
| REF 3 | ClinicalTrials.gov (NCT00914277) SAR407899 Single-dose in Treatment of Mild to Moderate Erectile Dysfunction. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT00767793) A Placebo-Controlled Study of INS117548 Ophthalmic Solution in Subjects With Glaucoma (P08650). U.S. National Institutes of Health. | |||||
| REF 5 | Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007 Jan;320(1):89-98. | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025959) | |||||
| REF 7 | Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19. | |||||
| REF 8 | The novel and specific Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol Ther. 2002 Feb-Mar;93(2-3):225-32. | |||||
| REF 9 | The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. J Hypertens. 2012 May;30(5):980-9. | |||||
| REF 10 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 11 | Rho kinase inhibitors: a patent review (2014 - 2016).Expert Opin Ther Pat. 2017 Apr;27(4):507-515. | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025959) | |||||
| REF 13 | Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22. | |||||
| REF 14 | Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47. | |||||
| REF 15 | Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res. 2004 Jan 9;94(1):46-52. | |||||
| REF 16 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1503). | |||||
| REF 17 | Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. | |||||
| REF 18 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 19 | Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo. Cardiovasc Res. 2001 Jul;51(1):169-77. | |||||
| REF 20 | Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem. 2009 May 1;17(9):3342-51. | |||||
| REF 21 | Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3235-9. | |||||
| REF 22 | Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J Med Chem. 2010 Aug 12;53(15):5727-37. | |||||
| REF 23 | Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun 1;3(6):699-709. | |||||
| REF 24 | Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-o... J Med Chem. 2008 Sep 25;51(18):5663-79. | |||||
| REF 25 | The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J Biol Chem. 2006 Jan 6;281(1):260-8. | |||||
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