Target Information
| Target General Information | Top | |||||
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| Target ID |
T61581
(Former ID: TTDS00424)
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| Target Name |
Guanylate cyclase soluble beta-1 (GUCY1B1)
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| Synonyms |
Soluble guanylate cyclase small subunit; Guanylate cyclase soluble subunit beta-3; Guanylate cyclase soluble subunit beta-1; GUCY1B3; GUCSB3; GUC1B3; GCS-beta-3; GCS-beta-1
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| Gene Name |
GUCY1B1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Heart failure [ICD-11: BD10-BD1Z] | |||||
| Function |
Mediates responses to nitric oxide (NO) by catalyzing the biosynthesis of the signaling molecule cGMP.
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| BioChemical Class |
Phosphorus-oxygen lyase
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| UniProt ID | ||||||
| EC Number |
EC 4.6.1.2
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| Sequence |
MYGFVNHALELLVIRNYGPEVWEDIKKEAQLDEEGQFLVRIIYDDSKTYDLVAAASKVLN
LNAGEILQMFGKMFFVFCQESGYDTILRVLGSNVREFLQNLDALHDHLATIYPGMRAPSF RCTDAEKGKGLILHYYSEREGLQDIVIGIIKTVAQQIHGTEIDMKVIQQRNEECDHTQFL IEEKESKEEDFYEDLDRFEENGTQESRISPYTFCKAFPFHIIFDRDLVVTQCGNAIYRVL PQLQPGNCSLLSVFSLVRPHIDISFHGILSHINTVFVLRSKEGLLDVEKLECEDELTGTE ISCLRLKGQMIYLPEADSILFLCSPSVMNLDDLTRRGLYLSDIPLHDATRDLVLLGEQFR EEYKLTQELEILTDRLQLTLRALEDEKKKTDTLLYSVLPPSVANELRHKRPVPAKRYDNV TILFSGIVGFNAFCSKHASGEGAMKIVNLLNDLYTRFDTLTDSRKNPFVYKVETVGDKYM TVSGLPEPCIHHARSICHLALDMMEIAGQVQVDGESVQITIGIHTGEVVTGVIGQRMPRY CLFGNTVNLTSRTETTGEKGKINVSEYTYRCLMSPENSDPQFHLEHRGPVSMKGKKEPMQ VWFLSRKNTGTEETKQDDD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T87CV3 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Cinaciguat | Drug Info | Phase 2 | Acute decompensated heart failure | [2], [3] | |
| 2 | Vericigiuat | Drug Info | Phase 2 | Heart failure | [4] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | RIG-200 | Drug Info | Discontinued in Phase 1 | Hypertension | [5] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | Cinaciguat | Drug Info | [6] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Vericigiuat | Drug Info | [1], [7] | |||
| 2 | RIG-200 | Drug Info | [8] | |||
| 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: Riociguat | Ligand Info | |||||
| Structure Description | Structure of huamn soluble guanylate cyclase in the riociguat and NO-bound state | PDB:7D9R | ||||
| Method | Electron microscopy | Resolution | 3.70 Å | Mutation | Yes | [9] |
| PDB Sequence |
MYGFVNHALE
10 LLVIRNYGPE20 VWEDIKKEAQ30 LDEEGQFLVR40 IIYDDSKTYD50 LVAAASKVLN 60 LNAGEILQMF70 GKMFFVFCQE80 SGYDTILRVL90 GSNVREFLQN100 LDALHDHLAT 110 IYPGMRAPSF120 RCTDAEKGKG130 LILHYYSERE140 GLQDIVIGII150 KTVAQQIHGT 160 EIDMKVIQQR170 NEECDHTQFL180 IEEKEESRIS209 PYTFCKAFPF219 HIIFDRDLVV 229 TQCGNAIYRV239 LPQLQPGNCS249 LLSVFSLVRP259 HIDISFHGIL269 SHINTVFVLR 279 SKEGLLDSCL304 RLKGQMIYLP314 EADSILFLCS324 PSVMNLDDLT334 RRGLYLSDIP 344 LHDATRDLVL354 LGEQFREEYK364 LTQELEILTD374 RLQLTLRALE384 DEKKKTDTLL 394 YSVLPPSVAN404 ELRHKRPVPA414 KRYDNVTILF424 SGIVGFNAFC434 SKHAGAMKIV 447 NLLNDLYTRF457 DTLTDSRKNP467 FVYKVETVGD477 KYMTVSGLPE487 PCIHHARSIC 497 HLALDMMEIA507 GQVQVDGESV517 QITIGIHTGE527 VVTGVIGQRM537 PRYCLFGNTV 547 NLTSRTETTG557 EKGKINVSEY567 TYRCLMSPEN577 SDPQFHLEHR587 GPVSMKGKKE 597 PMQVWFLSR
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| Ligand Name: Cinaciguat | Ligand Info | |||||
| Structure Description | Structure of human soluble guanylate cyclase in the cinciguat-bound activated state | PDB:7D9U | ||||
| Method | Electron microscopy | Resolution | 3.80 Å | Mutation | Yes | [9] |
| PDB Sequence |
MYGFVNHALE
10 LLVIRNYGPE20 VWEDIKKEAQ30 LDEEGQFLVR40 IIYDDSKTYD50 LVAAASKVLN 60 LNAGEILQMF70 GKMFFVFCQE80 SGYDTILRVL90 GSNVREFLQN100 LDALHDHLAT 110 IYPGMRAPSF120 RCTDAEKGKG130 LILHYYSERE140 GLQDIVIGII150 KTVAQQIHGT 160 EIDMKVIQQR170 NEECDHTQFL180 IEEKEESRIS209 PYTFCKAFPF219 HIIFDRDLVV 229 TQCGNAIYRV239 LPQLQPGNCS249 LLSVFSLVRP259 HIDISFHGIL269 SHINTVFVLR 279 SKEGLLDSCL304 RLKGQMIYLP314 EADSILFLCS324 PSVMNLDDLT334 RRGLYLSDIP 344 LHDATRDLVL354 LGEQFREEYK364 LTQELEILTD374 RLQLTLRALE384 DEKKKTDTLL 394 YSVLPPSVAN404 ELRHKRPVPA414 KRYDNVTILF424 SGIVGFNAFC434 SKHAGAMKIV 447 NLLNDLYTRF457 DTLTDSRKNP467 FVYKVETVGD477 KYMTVSGLPE487 PCIHHARSIC 497 HLALDMMEIA507 GQVQVDGESV517 QITIGIHTGE527 VVTGVIGQRM537 PRYCLFGNTV 547 NLTSRTETTG557 EKGKINVSEY567 TYRCLMSPEN577 SDPQFHLEHR587 GPVSMKGKKE 597 PMQVWFLSR
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MET1
3.644
TYR2
3.425
PHE4
3.307
VAL5
3.630
VAL39
4.061
ARG40
4.413
PHE74
3.731
CYS78
4.260
TYR83
3.869
ILE86
4.735
LEU87
4.267
LEU101
4.268
LEU104
4.760
HIS105
3.030
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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There is no similarity protein (E value < 0.005) for this target
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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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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| cGMP-PKG signaling pathway | hsa04022 | 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 | ||
| Gap junction | hsa04540 | 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 | ||
| Circadian entrainment | hsa04713 | Affiliated Target |
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| Class: Organismal Systems => Environmental adaptation | Pathway Hierarchy | ||
| Long-term depression | hsa04730 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Oxytocin signaling pathway | hsa04921 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Renin secretion | hsa04924 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Salivary secretion | hsa04970 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.07E-04 | Radiality | 3.98E-03 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+00 | Topological coefficient | . | Eccentricity | 1 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 9 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | cGMP-PKG signaling pathway | |||||
| 3 | Vascular smooth muscle contraction | |||||
| 4 | Gap junction | |||||
| 5 | Platelet activation | |||||
| 6 | Circadian entrainment | |||||
| 7 | Long-term depression | |||||
| 8 | Oxytocin signaling pathway | |||||
| 9 | Salivary secretion | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | IL4 Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Endothelin signaling pathway | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Purine Metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Nitric oxide stimulates guanylate cyclase | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Platelet homeostasis | |||||
| References | Top | |||||
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| REF 1 | Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur J Heart Fail. 2014 Sep;16(9):1026-38. | |||||
| REF 2 | 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. (Ligand id: 5168). | |||||
| REF 3 | ClinicalTrials.gov (NCT00559650) Placebo Controlled, Randomized, Double-blind, Multi-center Study to Investigate the Efficacy and Tolerability of BAY58-2667. U.S. National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of Bayer HealthCare Pharmaceuticals. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011948) | |||||
| REF 6 | Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. 2009 Jun 2;119(21):2781-8. | |||||
| REF 7 | Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol. 2013;218:279-313. | |||||
| REF 8 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 9 | Activation mechanism of human soluble guanylate cyclase by stimulators and activators. Nat Commun. 2021 Sep 17;12(1):5492. | |||||
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