Target Information

Target General Information

Target ID

T13491 (Former ID: TTDS00430)

Target Name

Solute carrier family 29 member 1 (SLC29A1)

Synonyms

SLC29A1; Nucleoside transporter, es-type; Nucleoside transporter 1; Equilibrative nitrobenzylmercaptopurine riboside-sensitive nucleoside transporter; Equilibrative NBMPR-sensitive nucleoside transporter; ENT1

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Gene Name

SLC29A1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Angina pectoris [ICD-11: BA40]

Function

Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (nbmpr) and is sodium-independent.

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UniProt ID

S29A1_HUMAN

Sequence

MTTSHQPQDRYKAVWLIFFMLGLGTLLPWNFFMTATQYFTNRLDMSQNVSLVTAELSKDA
QASAAPAAPLPERNSLSAIFNNVMTLCAMLPLLLFTYLNSFLHQRIPQSVRILGSLVAIL
LVFLITAILVKVQLDALPFFVITMIKIVLINSFGAILQGSLFGLAGLLPASYTAPIMSGQ
GLAGFFASVAMICAIASGSELSESAFGYFITACAVIILTIICYLGLPRLEFYRYYQQLKL
EGPGEQETKLDLISKGEEPRAGKEESGVSVSNSQPTNESHSIKAILKNISVLAFSVCFIF
TITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTFNIFDWLGRSLTAVFMWPGKDSRW
LPSLVLARLVFVPLLLLCNIKPRRYLTVVFEHDAWFIFFMAAFAFSNGYLASLCMCFGPK
KVKPAEAETAGAIMAFFLCLGLALGAVFSFLFRAIV

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

LIDOFLAZINE

Drug Info

Approved

Angina pectoris

[2]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 9 Inhibitor drugs

LIDOFLAZINE

Drug Info

[1]

6-(4-Nitro-benzylsulfanyl)-9-phenethyl-9H-purine

Drug Info

[3]

9-Benzyl-6-(4-nitro-benzylsulfanyl)-9H-purine

Drug Info

[3]

Dilazep

Drug Info

[4]

KF24345

Drug Info

[5]

N6-CYCLOPENTYLADENOSINE

Drug Info

[6]

NBTGR

Drug Info

[7]

Nitrobenzylthioinosine

Drug Info

[8]

S6-nitrobenzyl mercaptopurine riboside

Drug Info

[9]

Modulator

[+] 1 Modulator drugs

[3H]nitrobenzylmercaptopurine ribonucleoside

Drug Info

[7]

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: Dilazep

Ligand Info

Structure Description

Human equilibrative nucleoside transporter-1, dilazep bound

PDB:6OB7

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

Yes

[10]

PDB Sequence

PQDRYKAVWL

¹⁶

IFFMLGLGTL

²⁶

LPWNFFMTAT

³⁶

QYFTNRLDMS

⁴⁶

QNNSLSAIFN

⁸¹

NVMTLCAMLP

⁹¹

LLLFTYLNSF

¹⁰¹

LHQRIPQSVR

¹¹¹

ILGSLVAILL

¹²¹

VFLITAILVK

¹³¹

VQLDALPFFV

¹⁴¹

ITMIKIVLIN

¹⁵¹

SFGAILQGSL

¹⁶¹

FGLAGLFPAS

¹⁷¹

YTAAIMSGQG

¹⁸¹

LAGFFASVAM

¹⁹¹

ICAIASGSEL

²⁰¹

SESAFGYFIT

²¹¹

ACAVIILTII

²²¹

CYLGLPRLEF

²³¹

YRYYQQLKLS

²⁸¹

IKAILKKISV

²⁹¹

LAFSVCFIFT

³⁰¹

ITIGMFPAVT

³¹¹

VEVKSSIAGS

³²¹

STWERYFIPV

³³¹

SCFLTFNIFD

³⁴¹

WLGRSLTAVF

³⁵¹

MWPGKDSRWL

³⁶¹

PSLVLARLVF

³⁷¹

VPLLLLCNIK

³⁸¹

PRRYLTVVFE

³⁹¹

HDAWFIFFMA

⁴⁰¹

AFAFSNGYLA

⁴¹¹

SLCMCFGPKK

⁴²¹

VKPAEAETAG

⁴³¹

AIMAFFLCLG

⁴⁴¹

LALGAVFSFL

⁴⁵¹

Residue

Distance (Å)

THR25

4.937

LEU26

2.522

TRP29

1.981

ASN30

2.970

MET33

2.217

THR34

2.008

THR36

2.603

ASN81

3.550

MET84

2.226

THR85

2.687

ALA88

3.530

MET89

2.611

LEU92

2.722

ASN151

3.044

GLY154

3.801

GLN158

2.299

PHE162

3.957

GLN180

3.519

ALA183

4.637

Residue

Distance (Å)

GLY184

2.313

ALA187

2.751

SER188

2.371

MET191

2.736

PHE300

2.517

ILE304

2.286

PHE307

2.828

PRO308

2.704

ALA309

4.616

PHE334

2.808

PHE337

4.358

ASN338

2.556

ARG345

2.800

ASN407

4.267

LEU438

2.224

CYS439

3.774

LEU442

2.387

ALA446

3.304

Ligand Name: S6-nitrobenzyl mercaptopurine riboside

Ligand Info

Structure Description

Human equilibrative nucleoside transporter-1, S-(4-nitrobenzyl)-6-thioinosine bound, merohedrally twinned

PDB:6OB6

Method

X-ray diffraction

Resolution

2.90 Å

Mutation

Yes

[10]

PDB Sequence

PQDRYKAVWL

¹⁶

IFFMLGLGTL

²⁶

LPWNFFMTAT

³⁶

QYFTNRLDMN

⁷⁴

SLSAIFNNVM

⁸⁴

TLCAMLPLLL

⁹⁴

FTYLNSFLHQ

¹⁰⁴

RIPQSVRILG

¹¹⁴

SLVAILLVFL

¹²⁴

ITAILVKVQL

¹³⁴

DALPFFVITM

¹⁴⁴

IKIVLINSFG

¹⁵⁴

AILQGSLFGL

¹⁶⁴

AGLFPASYTA

¹⁷⁴

AIMSGQGLAG

¹⁸⁴

FFASVAMICA

¹⁹⁴

IASGSELSES

²⁰⁴

AFGYFITACA

²¹⁴

VIILTIICYL

²²⁴

GLPRLEFYRY

²³⁴

YQQSIKAILK

²⁸⁷

KISVLAFSVC

²⁹⁷

FIFTITIGMF

³⁰⁷

PAVTVEVKSS

³¹⁷

RYFIPVSCFL

³³⁵

TFNIFDWLGR

³⁴⁵

SLTAVFMWPG

³⁵⁵

KDSRWLPSLV

³⁶⁵

LARLVFVPLL

³⁷⁵

LLCNIKPRRY

³⁸⁵

LTVVFEHDAW

³⁹⁵

FIFFMAAFAF

⁴⁰⁵

SNGYLASLCM

⁴¹⁵

CFGPKKVKPA

⁴²⁵

EAETAGAIMA

⁴³⁵

FFLCLGLALG

⁴⁴⁵

AVFSF

Residue

Distance (Å)

GLY24

3.614

THR25

2.741

LEU26

2.072

PRO28

3.118

TRP29

2.324

ASN30

4.484

MET33

4.028

MET89

4.334

LEU92

2.372

LEU116

4.622

ILE119

2.406

PHE123

4.290

ILE150

2.548

ASN151

3.092

GLY154

2.564

ALA155

4.193

Residue

Distance (Å)

LEU157

2.327

GLN158

2.201

PHE162

4.482

GLN180

3.030

GLY181

4.825

PHE300

2.045

THR303

2.391

ILE304

2.431

PHE307

2.748

PHE337

1.962

ASP341

3.138

ARG345

2.518

ASN407

3.210

LEU438

3.126

CYS439

4.725

LEU442

3.192

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 Similarity Proteins Human Tissue Distribution

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 Similarity Proteins

Human Tissue Distribution

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.

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

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibit... J Med Chem. 2007 Aug 9;50(16):3906-20.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

Inhibition of nucleoside transport by new analogues of 4-nitrobenzylthioinosine: replacement of the ribose moiety by substituted benzyl groups. J Med Chem. 2004 Oct 21;47(22):5441-50.

REF 4

Residues Met89 and Ser160 in the human equilibrative nucleoside transporter 1 affect its affinity for adenosine, guanosine, S6-(4-nitrobenzyl)-merc... Mol Pharmacol. 2005 Mar;67(3):837-44.

REF 5

Interaction of the novel adenosine uptake inhibitor 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazol... J Pharmacol Exp Ther. 2004 Mar;308(3):1083-93.

REF 6

Inhibition of nucleoside transport proteins by C8-alkylamine-substituted purines. J Med Chem. 2005 Jan 13;48(1):321-9.

REF 7

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: 1117).

REF 8

The role of human nucleoside transporters in uptake of 3'-deoxy-3'-fluorothymidine. Mol Pharmacol. 2008 Nov;74(5):1372-80.

REF 9

Synthesis and biological evaluation of phloridzin analogs as human concentrative nucleoside transporter 3 (hCNT3) inhibitors. Bioorg Med Chem Lett. 2009 Feb 1;19(3):917-21.

REF 10

Structures of human ENT1 in complex with adenosine reuptake inhibitors. Nat Struct Mol Biol. 2019 Jul;26(7):599-606.

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