Target Information

Target General Information

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Target ID

T92403 (Former ID: TTDR00035)

Target Name

Sodium/hydrogen exchanger 3 (SLC9A3)

Synonyms

SLC9A3; Na(+)/H(+) exchanger 3; NHE-3

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Gene Name

SLC9A3

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Irritable bowel syndrome [ICD-11: DD91]

Function

Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.

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BioChemical Class

Monovalent cation:proton antiporter

UniProt ID

SL9A3_HUMAN

Sequence

MWGLGARGPDRGLLLALALGGLARAGGVEVEPGGAHGESGGFQVVTFEWAHVQDPYVIAL
WILVASLAKIGFHLSHKVTSVVPESALLIVLGLVLGGIVWAADHIASFTLTPTVFFFYLL
PPIVLDAGYFMPNRLFFGNLGTILLYAVVGTVWNAATTGLSLYGVFLSGLMGDLQIGLLD
FLLFGSLMAAVDPVAVLAVFEEVHVNEVLFIIVFGESLLNDAVTVVLYNVFESFVALGGD
NVTGVDCVKGIVSFFVVSLGGTLVGVVFAFLLSLVTRFTKHVRIIEPGFVFIISYLSYLT
SEMLSLSAILAITFCGICCQKYVKANISEQSATTVRYTMKMLASSAETIIFMFLGISAVN
PFIWTWNTAFVLLTLVFISVYRAIGVVLQTWLLNRYRMVQLEPIDQVVLSYGGLRGAVAF
ALVVLLDGDKVKEKNLFVSTTIIVVFFTVIFQGLTIKPLVQWLKVKRSEHREPRLNEKLH
GRAFDHILSAIEDISGQIGHNYLRDKWSHFDRKFLSRVLMRRSAQKSRDRILNVFHELNL
KDAISYVAEGERRGSLAFIRSPSTDNVVNVDFTPRSSTVEASVSYLLRENVSAVCLDMQS
LEQRRRSIRDAEDMVTHHTLQQYLYKPRQEYKHLYSRHELTPTEDEKQDREIFHRTMRKR
LESFKSTKLGLNQNKKAAKLYKRERAQKRRNSSIPNGKLPMESPAQNFTIKEKDLELSDT
EEPPNYDEEMSGGIEFLASVTKDTASDSPAGIDNPVFSPDEALDRSLLARLPPWLSPGET
VVPSQRARTQIPYSPGTFCRLMPFRLSSKSVDSFLQADGPEERPPAALPESTHM

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3D Structure

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AlphaFold

HIT2.0 ID

T09HVO

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Tenapanor

Drug Info

Approved

Irritable bowel syndrome

[2]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

AVE-0657

Drug Info

Phase 2

Cheyne-stokes respiration

[3]

AZD1772//RDX5791

Drug Info

Phase 2

Chronic kidney disease

[4]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

CARIPORIDE

Drug Info

Discontinued in Phase 2

Angina pectoris

[5]

ENIPORIDE

Drug Info

Discontinued in Phase 2

Cardiac arrhythmias

[6]

HOE-694

Drug Info

Terminated

Heart arrhythmia

[7]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 2 Modulator drugs

Tenapanor

Drug Info

[2]

AZD1772//RDX5791

Drug Info

[1]

Inhibitor

[+] 10 Inhibitor drugs

AVE-0657

Drug Info

[8]

CARIPORIDE

Drug Info

[9]

ENIPORIDE

Drug Info

[9]

HOE-694

Drug Info

[10]

N-(3-Methanesulfonyl-4-methoxy-benzoyl)-guanidine

Drug Info

[10]

N-(3-Methanesulfonyl-4-methyl-benzoyl)-guanidine

Drug Info

[10]

N-(4-Bromo-3-methanesulfonyl-benzoyl)-guanidine

Drug Info

[10]

N-(4-Chloro-3-methanesulfonyl-benzoyl)-guanidine

Drug Info

[10]

N-(4-Cyano-3-methanesulfonyl-benzoyl)-guanidine

Drug Info

[10]

N-(5-Methanesulfonyl-2-methyl-benzoyl)-guanidine

Drug Info

[10]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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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 NHE3-CHP1 complex in the autoinhibited state

PDB:7X2U

Method

Electron microscopy

Resolution

3.20 Å

Mutation

[11]

PDB Sequence

GGFQVVTFEW

⁴⁹

AHVQDPYVIA

⁵⁹

LWILVASLAK

⁶⁹

IGFHLSHKVT

⁷⁹

SVVPESALLI

⁸⁹

VLGLVLGGIV

⁹⁹

WAADHIASFT

¹⁰⁹

LTPTVFFFYL

¹¹⁹

LPPIVLDAGY

¹²⁹

FMPNRLFFGN

¹³⁹

LGTILLYAVV

¹⁴⁹

GTVWNAATTG

¹⁵⁹

LSLYGVFLSG

¹⁶⁹

LMGDLQIGLL

¹⁷⁹

DFLLFGSLMA

¹⁸⁹

AVDPVAVLAV

¹⁹⁹

FEEVHVNEVL

²⁰⁹

FIIVFGESLL

²¹⁹

NDAVTVVLYN

²²⁹

VFESFVALGG

²³⁹

DNVTGVDCVK

²⁴⁹

GIVSFFVVSL

²⁵⁹

GGTLVGVVFA

²⁶⁹

FLLSLVTRFT

²⁷⁹

KHVRIIEPGF

²⁸⁹

VFIISYLSYL

²⁹⁹

TSEMLSLSAI

³⁰⁹

LAITFCGICC

³¹⁹

QKYVKANISE

³²⁹

QSATTVRYTM

³³⁹

KMLASSAETI

³⁴⁹

IFMFLGISAV

³⁵⁹

NPFIWTWNTA

³⁶⁹

FVLLTLVFIS

³⁷⁹

VYRAIGVVLQ

³⁸⁹

TWLLNRYRMV

³⁹⁹

QLEPIDQVVL

⁴⁰⁹

SYGGLRGAVA

⁴¹⁹

FALVVLLDGD

⁴²⁹

KVKEKNLFVS

⁴³⁹

TTIIVVFFTV

⁴⁴⁹

IFQGLTIKPL

⁴⁵⁹

VQWLKVRLNE

⁴⁷⁷

KLHGRAFDHI

⁴⁸⁷

LSAIEDISGQ

⁴⁹⁷

IGHNYLRDKW

⁵⁰⁷

SHFDRKFLSR

⁵¹⁷

VLMRRSAQKS

⁵²⁷

RDRILNVFHE

⁵³⁷

LNHHTLQQYL

⁶²⁴

YKPRQEYKHL

⁶³⁴

YSRHELTPTE

⁶⁴⁴

DEKQDREIFH

⁶⁵⁴

RTMRKRLESF

⁶⁶⁴

Residue

Distance (Å)

TRP49

4.017

GLN53

3.422

ASP54

3.547

VAL57

3.786

ILE58

3.939

LEU60

4.601

TRP61

3.906

ILE62

4.057

LEU95

4.049

ILE98

3.952

VAL99

3.756

ALA102

3.955

HIS104

3.735

SER107

3.565

PHE108

3.444

THR109

3.647

THR111

4.307

THR113

4.253

Residue

Distance (Å)

VAL114

3.593

PHE117

3.680

TYR118

3.284

LEU119

3.942

PRO121

4.098

PRO122

3.453

LEU125

2.898

PHE291

3.519

ILE292

3.797

SER294

4.906

TYR295

3.712

ILE312

3.952

MET341

3.388

LEU342

3.800

SER345

3.033

ALA346

3.929

ILE349

3.674

PHE353

4.196

Ligand Name: D-myo-Inositol 1-[(2R)-2,3-bis[(1-oxohexadecyl)oxy]propyl hydrogen phosphate]

Ligand Info

Structure Description

Structure of a human NHE3-CHP1 complex in the autoinhibited state

PDB:7X2U

Method

Electron microscopy

Resolution

3.20 Å

Mutation

[11]

PDB Sequence

GGFQVVTFEW

⁴⁹

AHVQDPYVIA

⁵⁹

LWILVASLAK

⁶⁹

IGFHLSHKVT

⁷⁹

SVVPESALLI

⁸⁹

VLGLVLGGIV

⁹⁹

WAADHIASFT

¹⁰⁹

LTPTVFFFYL

¹¹⁹

LPPIVLDAGY

¹²⁹

FMPNRLFFGN

¹³⁹

LGTILLYAVV

¹⁴⁹

GTVWNAATTG

¹⁵⁹

LSLYGVFLSG

¹⁶⁹

LMGDLQIGLL

¹⁷⁹

DFLLFGSLMA

¹⁸⁹

AVDPVAVLAV

¹⁹⁹

FEEVHVNEVL

²⁰⁹

FIIVFGESLL

²¹⁹

NDAVTVVLYN

²²⁹

VFESFVALGG

²³⁹

DNVTGVDCVK

²⁴⁹

GIVSFFVVSL

²⁵⁹

GGTLVGVVFA

²⁶⁹

FLLSLVTRFT

²⁷⁹

KHVRIIEPGF

²⁸⁹

VFIISYLSYL

²⁹⁹

TSEMLSLSAI

³⁰⁹

LAITFCGICC

³¹⁹

QKYVKANISE

³²⁹

QSATTVRYTM

³³⁹

KMLASSAETI

³⁴⁹

IFMFLGISAV

³⁵⁹

NPFIWTWNTA

³⁶⁹

FVLLTLVFIS

³⁷⁹

VYRAIGVVLQ

³⁸⁹

TWLLNRYRMV

³⁹⁹

QLEPIDQVVL

⁴⁰⁹

SYGGLRGAVA

⁴¹⁹

FALVVLLDGD

⁴²⁹

KVKEKNLFVS

⁴³⁹

TTIIVVFFTV

⁴⁴⁹

IFQGLTIKPL

⁴⁵⁹

VQWLKVRLNE

⁴⁷⁷

KLHGRAFDHI

⁴⁸⁷

LSAIEDISGQ

⁴⁹⁷

IGHNYLRDKW

⁵⁰⁷

SHFDRKFLSR

⁵¹⁷

VLMRRSAQKS

⁵²⁷

RDRILNVFHE

⁵³⁷

LNHHTLQQYL

⁶²⁴

YKPRQEYKHL

⁶³⁴

YSRHELTPTE

⁶⁴⁴

DEKQDREIFH

⁶⁵⁴

RTMRKRLESF

⁶⁶⁴

Residue

Distance (Å)

GLY138

2.262

ASN139

3.339

LEU140

3.929

GLY141

3.145

THR142

2.894

LEU144

3.808

LEU145

3.763

VAL148

3.792

VAL149

3.985

VAL152

3.616

TRP153

4.602

PHE254

4.709

PHE255

3.701

Residue

Distance (Å)

LEU388

4.247

GLN389

4.771

LEU392

3.526

LEU393

3.333

TYR396

3.326

ARG397

3.340

MET398

2.948

VAL399

3.864

GLN497

2.542

ILE498

2.531

GLY499

4.414

HIS500

2.398

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

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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

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target
Proximal tubule bicarbonate reclamation	hsa04964	Affiliated Target
Class: Organismal Systems => Excretory system	Pathway Hierarchy
Protein digestion and absorption	hsa04974	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Bile secretion	hsa04976	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Mineral absorption	hsa04978	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	1.57E-04
Closeness centrality	2.10E-01	Radiality	1.37E+01	Clustering coefficient	1.33E-01
Neighborhood connectivity	1.82E+01	Topological coefficient	2.01E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 4 KEGG Pathways

Proximal tubule bicarbonate reclamation

Protein digestion and absorption

Bile secretion

Mineral absorption

PID Pathway

[+] 2 PID Pathways

Endothelins

RhoA signaling pathway

WikiPathways

[+] 1 WikiPathways

SIDS Susceptibility Pathways

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

RDX5791, a First-in-Class Minimally Systemic NHE3 Inhibitor in Clinical Development for CIC and IBS-C, Increases Intestinal Sodium Leading to Enhanced Intestinal Fluid Volume and Transit. Gastroenterology. 2011;140(suppl 1):S99.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019

REF 3

ClinicalTrials.gov (NCT00614250) Evaluation of the Effect of AVE0657 on Obstructive Sleep Apnea. U.S. National Institutes of Health.

REF 4

Clinical pipeline report, company report or official report of Ardelyx.

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 800004531)

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 800010029)

REF 7

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 8

Inhibition of central Na(+)/H(+) exchanger type 3 can alleviate sleep apnea in Sprague-Dawley rats. Chin Med J (Engl). 2014;127(1):48-53.

REF 9

Bicyclic acylguanidine Na+/H+ antiporter inhibitors. J Med Chem. 1998 Sep 10;41(19):3736-47.

REF 10

(2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. J Med Chem. 1997 Jun 20;40(13):2017-34.

REF 11

Structure of a human NHE3-CHP1 complex in the autoinhibited state

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