Target Information
| Target General Information | Top | |||||
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| Target ID |
T82028
(Former ID: TTDR00347)
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| Target Name |
Sodium/hydrogen exchanger 1 (SLC9A1)
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| Synonyms |
Solute carrier family 9 member 1; Na+/H+ antiporter, amiloride-sensitive; Na(+)Sodium/hydrogen exchanger 1/H(+) exchanger 1; Na(+)/H(+) exchanger 1; Na(+)/H(+) antiporter, amiloride-sensitive; NHE1; NHE-1; Myocardial Na+/H+ exchanger; APNH1; APNH
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| Gene Name |
SLC9A1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Angina pectoris [ICD-11: BA40] | |||||
| Function |
Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions.
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| BioChemical Class |
Monovalent cation:proton antiporter-1
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| UniProt ID | ||||||
| Sequence |
MVLRSGICGLSPHRIFPSLLVVVALVGLLPVLRSHGLQLSPTASTIRSSEPPRERSIGDV
TTAPPEVTPESRPVNHSVTDHGMKPRKAFPVLGIDYTHVRTPFEISLWILLACLMKIGFH VIPTISSIVPESCLLIVVGLLVGGLIKGVGETPPFLQSDVFFLFLLPPIILDAGYFLPLR QFTENLGTILIFAVVGTLWNAFFLGGLMYAVCLVGGEQINNIGLLDNLLFGSIISAVDPV AVLAVFEEIHINELLHILVFGESLLNDAVTVVLYHLFEEFANYEHVGIVDIFLGFLSFFV VALGGVLVGVVYGVIAAFTSRFTSHIRVIEPLFVFLYSYMAYLSAELFHLSGIMALIASG VVMRPYVEANISHKSHTTIKYFLKMWSSVSETLIFIFLGVSTVAGSHHWNWTFVISTLLF CLIARVLGVLGLTWFINKFRIVKLTPKDQFIIAYGGLRGAIAFSLGYLLDKKHFPMCDLF LTAIITVIFFTVFVQGMTIRPLVDLLAVKKKQETKRSINEEIHTQFLDHLLTGIEDICGH YGHHHWKDKLNRFNKKYVKKCLIAGERSKEPQLIAFYHKMEMKQAIELVESGGMGKIPSA VSTVSMQNIHPKSLPSERILPALSKDKEEEIRKILRNNLQKTRQRLRSYNRHTLVADPYE EAWNQMLLRRQKARQLEQKINNYLTVPAHKLDSPTMSRARIGSDPLAYEPKEDLPVITID PASPQSPESVDLVNEELKGKVLGLSRDPAKVAEEDEDDDGGIMMRSKETSSPGTDDVFTP APSDSPSSQRIQRCLSDPGPHPEPGEGEPFFPKGQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T49A2A | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Zoniporide hydrochloride | Drug Info | Phase 3 | Angina pectoris | [1] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | CARIPORIDE | Drug Info | Discontinued in Phase 2 | Angina pectoris | [2] | |
| 2 | ENIPORIDE | Drug Info | Discontinued in Phase 2 | Cardiac arrhythmias | [3] | |
| 3 | HOE-694 | Drug Info | Terminated | Heart arrhythmia | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 20 Inhibitor drugs | + | ||||
| 1 | Zoniporide hydrochloride | Drug Info | [1], [5] | |||
| 2 | CARIPORIDE | Drug Info | [6] | |||
| 3 | ENIPORIDE | Drug Info | [7] | |||
| 4 | HOE-694 | Drug Info | [8] | |||
| 5 | 5'-(N-ethyl-N-isopropyl)amiloride | Drug Info | [9] | |||
| 6 | BIIB-513 | Drug Info | [10] | |||
| 7 | Homoserine Lactone | Drug Info | [11] | |||
| 8 | N-(3-Methanesulfonyl-4-methoxy-benzoyl)-guanidine | Drug Info | [8] | |||
| 9 | N-(3-Methanesulfonyl-4-methyl-benzoyl)-guanidine | Drug Info | [8] | |||
| 10 | N-(4-Bromo-3-methanesulfonyl-benzoyl)-guanidine | Drug Info | [8] | |||
| 11 | N-(4-Chloro-3-methanesulfonyl-benzoyl)-guanidine | Drug Info | [8] | |||
| 12 | N-(4-Cyano-3-methanesulfonyl-benzoyl)-guanidine | Drug Info | [8] | |||
| 13 | N-(5-m-Tolyl-furan-2-carbonyl)-guanidine | Drug Info | [12] | |||
| 14 | N-(5-Methanesulfonyl-2-methyl-benzoyl)-guanidine | Drug Info | [8] | |||
| 15 | N-(5-o-Tolyl-furan-2-carbonyl)-guanidine | Drug Info | [12] | |||
| 16 | N-(5-Phenyl-furan-2-carbonyl)-guanidine | Drug Info | [12] | |||
| 17 | N-[2-(1H-benzoimidazol-2-yl)-benzoyl]-guanidine | Drug Info | [13] | |||
| 18 | N-[4-(1H-benzoimidazol-2-yl)-benzoyl]-guanidine | Drug Info | [13] | |||
| 19 | N-[5-(2-Ethyl-phenyl)-furan-2-carbonyl]-guanidine | Drug Info | [12] | |||
| 20 | N-[5-(2-Nitro-phenyl)-furan-2-carbonyl]-guanidine | Drug Info | [12] | |||
| 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: Cariporide | Ligand Info | |||||
| Structure Description | Structure of a human NHE1-CHP1 complex under pH 7.5, bound by cariporide | PDB:7DSX | ||||
| Method | Electron microscopy | Resolution | 3.50 Å | Mutation | Yes | [14] |
| PDB Sequence |
PRKAFPVLGI
94 DYTHVRTPFE104 ISLWILLACL114 MKIGFHVIPT124 ISSIVPESCL134 LIVVGLLVGG 144 LIKGVGETPP154 FLQSDVFFLF164 LLPPIILDAG174 YFLPLRQFTE184 NLGTILIFAV 194 VGTLWNAFFL204 GGLMYAVCLV214 GGEQINNIGL224 LDNLLFGSII234 SAVDPVAVLA 244 VFEEIHINEL254 LHILVFGESL264 LNDAVTVVLY274 HLFEEFANYE284 HVGIVDIFLG 294 FLSFFVVALG304 GVLVGVVYGV314 IAAFTSRFTS324 HIRVIEPLFV334 FLYSYMAYLS 344 AELFHLSGIM354 ALIASGVVMR364 PYVEANISHK374 SHTTIKYFLK384 MWSSVSETLI 394 FIFLGVSTVA404 GSHHWNWTFV414 ISTLLFCLIA424 RVLGVLGLTW434 FINKFRIVKL 444 TPKDQFIIAY454 GGLRGAIAFS464 LGYLLDKKHF474 PMCDLFLTAI484 ITVIFFTVFV 494 QGMTIRPLVD504 LLAVKKKQET514 KRSINEEIHT524 QFLDHLLTGI534 EDICGHYGHH 544 HWKDKLNRFN554 KKYVKKCLIA564 GERSKEPQLI574 AFYHKMEMKQ584 AIELVESGG |
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| Ligand Name: (1s)-2-{[{[(2r)-2,3-Dihydroxypropyl]oxy}(Hydroxy)phosphoryl]oxy}-1-[(Palmitoyloxy)methyl]ethyl Stearate | Ligand Info | |||||
| Structure Description | Structure of a human NHE1-CHP1 complex under pH 7.5, bound by cariporide | PDB:7DSX | ||||
| Method | Electron microscopy | Resolution | 3.50 Å | Mutation | Yes | [14] |
| PDB Sequence |
PRKAFPVLGI
94 DYTHVRTPFE104 ISLWILLACL114 MKIGFHVIPT124 ISSIVPESCL134 LIVVGLLVGG 144 LIKGVGETPP154 FLQSDVFFLF164 LLPPIILDAG174 YFLPLRQFTE184 NLGTILIFAV 194 VGTLWNAFFL204 GGLMYAVCLV214 GGEQINNIGL224 LDNLLFGSII234 SAVDPVAVLA 244 VFEEIHINEL254 LHILVFGESL264 LNDAVTVVLY274 HLFEEFANYE284 HVGIVDIFLG 294 FLSFFVVALG304 GVLVGVVYGV314 IAAFTSRFTS324 HIRVIEPLFV334 FLYSYMAYLS 344 AELFHLSGIM354 ALIASGVVMR364 PYVEANISHK374 SHTTIKYFLK384 MWSSVSETLI 394 FIFLGVSTVA404 GSHHWNWTFV414 ISTLLFCLIA424 RVLGVLGLTW434 FINKFRIVKL 444 TPKDQFIIAY454 GGLRGAIAFS464 LGYLLDKKHF474 PMCDLFLTAI484 ITVIFFTVFV 494 QGMTIRPLVD504 LLAVKKKQET514 KRSINEEIHT524 QFLDHLLTGI534 EDICGHYGHH 544 HWKDKLNRFN554 KKYVKKCLIA564 GERSKEPQLI574 AFYHKMEMKQ584 AIELVESGG |
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GLU104
3.920
ILE105
3.555
TRP108
3.434
ILE109
3.540
PRO154
4.102
VAL160
3.658
LEU163
4.434
PHE164
3.539
LEU165
3.854
PRO167
4.632
PRO168
4.442
LEU171
4.612
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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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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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| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Cardiac muscle contraction | hsa04260 | Affiliated Target |
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| Class: Organismal Systems => Circulatory system | Pathway Hierarchy | ||
| Adrenergic signaling in cardiomyocytes | hsa04261 | Affiliated Target |
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| Class: Organismal Systems => Circulatory system | Pathway Hierarchy | ||
| Apelin signaling pathway | hsa04371 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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| Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
| Thyroid hormone signaling pathway | hsa04919 | 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 | ||
| Gastric acid secretion | hsa04971 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Pancreatic secretion | hsa04972 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Bile secretion | hsa04976 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 8.33E-04 |
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| Closeness centrality | 2.21E-01 | Radiality | 1.39E+01 | Clustering coefficient | 4.76E-02 |
| Neighborhood connectivity | 2.79E+01 | Topological coefficient | 1.57E-01 | Eccentricity | 12 |
| 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 | ||
| 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 | ||||||
| Target Profiles in Patients | Top | |||||
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| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 10 KEGG Pathways | + | ||||
| 1 | cAMP signaling pathway | |||||
| 2 | Cardiac muscle contraction | |||||
| 3 | Adrenergic signaling in cardiomyocytes | |||||
| 4 | Regulation of actin cytoskeleton | |||||
| 5 | Thyroid hormone signaling pathway | |||||
| 6 | Salivary secretion | |||||
| 7 | Gastric acid secretion | |||||
| 8 | Pancreatic secretion | |||||
| 9 | Bile secretion | |||||
| 10 | Proteoglycans in cancer | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | Endothelins | |||||
| 2 | RhoA signaling pathway | |||||
| 3 | ErbB1 downstream signaling | |||||
| 4 | Signaling mediated by p38-alpha and p38-beta | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Hyaluronan uptake and degradation | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Regulation of Actin Cytoskeleton | |||||
| 2 | G Protein Signaling Pathways | |||||
| 3 | Glycosaminoglycan metabolism | |||||
| 4 | Osteoclast Signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Zoniporde: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1). Cardiovasc Drug Rev. 2003 Spring;21(1):17-32. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004531) | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010029) | |||||
| REF 4 | Effect of Hoe 694, a novel Na(+)-H+ exchange inhibitor, on intracellular pH regulation in the guinea-pig ventricular myocyte. Br J Pharmacol. 1996 Aug;118(8):1905-12. | |||||
| REF 5 | Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36. | |||||
| REF 6 | Synthesis and bioactivity of substituted indan-1-ylideneaminoguanidine derivatives. Eur J Med Chem. 2009 Sep;44(9):3771-6. | |||||
| REF 7 | Bicyclic acylguanidine Na+/H+ antiporter inhibitors. J Med Chem. 1998 Sep 10;41(19):3736-47. | |||||
| REF 8 | (2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. J Med Chem. 1997 Jun 20;40(13):2017-34. | |||||
| REF 9 | NHE1 inhibition by amiloride- and benzoylguanidine-type compounds. Inhibitor binding loci deduced from chimeras of NHE1 homologues with endogenous ... J Biol Chem. 2007 Jul 6;282(27):19716-27. | |||||
| REF 10 | 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: 948). | |||||
| REF 11 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 12 | (5-Arylfuran-2-ylcarbonyl)guanidines as cardioprotectives through the inhibition of Na+/H+ exchanger isoform-1. J Med Chem. 2005 Apr 21;48(8):2882-91. | |||||
| REF 13 | Benzimidazol-2-yl or benzimidazol-2-ylthiomethyl benzoylguanidines as novel Na+/H+ exchanger inhibitors, synthesis and protection against ischemic-... Bioorg Med Chem Lett. 2007 May 1;17(9):2430-3. | |||||
| REF 14 | Structure and mechanism of the human NHE1-CHP1 complex. Nat Commun. 2021 Jun 9;12(1):3474. | |||||
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