Target Information

Target General Information

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Target ID

T91661 (Former ID: TTDR00529)

Target Name

Adenosine kinase (ADK)

Synonyms

Adenosine 5'-phosphotransferase; AK

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Gene Name

ADK

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Epilepsy/seizure [ICD-11: 8A61-8A6Z]

Function

Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides. ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives.

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BioChemical Class

Kinase

UniProt ID

ADK_HUMAN

EC Number

EC 2.7.1.20

Sequence

MAAAEEEPKPKKLKVEAPQALRENILFGMGNPLLDISAVVDKDFLDKYSLKPNDQILAED
KHKELFDELVKKFKVEYHAGGSTQNSIKVAQWMIQQPHKAATFFGCIGIDKFGEILKRKA
AEAHVDAHYYEQNEQPTGTCAACITGDNRSLIANLAAANCYKKEKHLDLEKNWMLVEKAR
VCYIAGFFLTVSPESVLKVAHHASENNRIFTLNLSAPFISQFYKESLMKVMPYVDILFGN
ETEAATFAREQGFETKDIKEIAKKTQALPKMNSKRQRIVIFTQGRDDTIMATESEVTAFA
VLDQDQKEIIDTNGAGDAFVGGFLSQLVSDKPLTECIRAGHYAASIIIRRTGCTFPEKPD
FH

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

GP-3269

Drug Info

Phase 1

Convulsion

[1]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

A-134974

Drug Info

Terminated

Epilepsy

[2], [3]

ABT-702

Drug Info

Terminated

Pain

[4], [5]

GP-683

Drug Info

Terminated

Pain

[6]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 10 Inhibitor drugs

GP-3269

Drug Info

[1]

A-134974

Drug Info

[7]

ABT-702

Drug Info

[8]

GP-683

Drug Info

[9]

5'-iodotubercidin

Drug Info

[10]

5-iodo,5'-deoxytubercidin

Drug Info

[11]

6-Benzylthioinosine

Drug Info

[12]

GP515

Drug Info

[13]

Iodotubercidin

Drug Info

[14]

MB-03966

Drug Info

[15]

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: Adenosine

Ligand Info

Structure Description

STRUCTURE OF HUMAN ADENOSINE KINASE AT 1.50 ANGSTROMS

PDB:1BX4

Method

X-ray diffraction

Resolution

1.50 Å

Mutation

[16]

PDB Sequence

VRENILFGMG

¹³

NPLLDISAVV

²³

DKDFLDKYSL

³³

KPNDQILAED

⁴³

KHKELFDELV

⁵³

KKFKVEYHAG

⁶³

GSTQNSIKVA

⁷³

QWMIQQPHKA

⁸³

ATFFGCIGID

⁹³

KFGEILKRKA

¹⁰³

AEAHVDAHYY

¹¹³

EQNEQPTGTC

¹²³

AACITGDNRS

¹³³

LIANLAAANC

¹⁴³

YKKEKHLDLE

¹⁵³

KNWMLVEKAR

¹⁶³

VCYIAGFFLT

¹⁷³

VSPESVLKVA

¹⁸³

HHASENNRIF

¹⁹³

TLNLSAPFIS

²⁰³

QFYKESLMKV

²¹³

MPYVDILFGN

²²³

ETEAATFARE

²³³

QGFETKDIKE

²⁴³

IAKKTQALPK

²⁵³

MNSKRQRIVI

²⁶³

FTQGRDDTIM

²⁷³

ATESEVTAFA

²⁸³

VLDQDQKEII

²⁹³

DTNGAGDAFV

³⁰³

GGFLSQLVSD

³¹³

KPLTECIRAG

³²³

HYAASIIIRR

³³³

TGCTFPEKPD

³⁴³

Residue

Distance (Å)

ASN14

3.121

LEU16

3.714

ASP18

2.723

GLN38

3.915

LEU40

3.652

GLY63

3.801

GLY64

3.130

SER65

3.195

ASN68

3.105

CYS123

3.805

LEU134

4.089

ALA136

3.772

LEU138

3.876

PHE170

3.403

PHE201

4.379

THR265

3.594

GLN266

4.709

Residue

Distance (Å)

GLY267

3.379

ARG268

3.510

THR271

3.571

VAL284

3.733

ASP286

3.377

GLN289

2.988

ILE292

3.516

THR295

4.151

ASN296

3.227

GLY297

3.672

ALA298

3.582

GLY299

3.694

ASP300

2.793

PHE302

4.340

HIS324

3.475

ALA327

3.483

ILE331

3.489

Ligand Name: 5-iodo,5'-deoxytubercidin

Ligand Info

Structure Description

Human Adenosine Kinase in Complex With 5'-Deoxy-5-Iodotubercidin

PDB:2I6A

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[11]

PDB Sequence

SVRENILFGM

¹²

GNPLLDISAV

²²

VDKDFLDKYS

³²

LKPNDQILAE

⁴²

DKHKELFDEL

⁵²

VKKFKVEYHA

⁶²

GGSTQNSIKV

⁷²

AQWMIQQPHK

⁸²

AATFFGCIGI

⁹²

DKFGEILKRK

¹⁰²

AAEAHVDAHY

¹¹²

YEQNEQPTGT

¹²²

CAACITGDNR

¹³²

SLIANLAAAN

¹⁴²

CYKKEKHLDL

¹⁵²

EKNWMLVEKA

¹⁶²

RVCYIAGFFL

¹⁷²

TVSPESVLKV

¹⁸²

AHHASENNRI

¹⁹²

FTLNLSAPFI

²⁰²

SQFYKESLMK

²¹²

VMPYVDILFG

²²²

NETEAATFAR

²³²

EQGFETKDIK

²⁴²

EIAKKTQALP

²⁵²

KMNSKRQRIV

²⁶²

IFTQGRDDTI

²⁷²

MATESEVTAF

²⁸²

AVLDQDQKEI

²⁹²

IDTNGAGDAF

³⁰²

VGGFLSQLVS

³¹²

DKPLTECIRA

³²²

GHYAASIIIR

³³²

RTGCTFPEKP

³⁴²

DFH

Residue

Distance (Å)

ASN14

2.999

LEU16

4.027

ASP18

2.588

GLN38

4.019

ILE39

3.597

LEU40

3.137

GLY63

3.442

GLY64

3.150

SER65

3.074

ASN68

2.836

CYS123

3.667

Residue

Distance (Å)

LEU134

3.781

ILE135

4.940

ALA136

3.861

LEU138

3.993

PHE170

3.216

PHE201

4.320

ASP294

4.347

ASN296

3.524

GLY297

3.909

ASP300

3.532

ARG332

4.241

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	Pathway Map
Purine metabolism	hsa00230	Affiliated Target
Class: Metabolism => Nucleotide metabolism	Pathway Hierarchy

Degree	16	Degree centrality	1.72E-03	Betweenness centrality	1.52E-03
Closeness centrality	1.78E-01	Radiality	1.29E+01	Clustering coefficient	1.08E-01
Neighborhood connectivity	5.56E+00	Topological coefficient	1.15E-01	Eccentricity	13
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 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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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

Superpathway of purine nucleotide salvage

Adenine and adenosine salvage II

KEGG Pathway

[+] 2 KEGG Pathways

Purine metabolism

Metabolic pathways

Reactome

[+] 1 Reactome Pathways

Purine salvage

WikiPathways

[+] 1 WikiPathways

Metabolism of nucleotides

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Adenosine kinase inhibitors. 6. Synthesis, water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides andrelated compounds. J Med Chem. 2005 Dec 1;48(24):7808-20.

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: 5130).

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 800009094)

REF 4

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 800014976)

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 800006618)

REF 7

Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action. J Pharmacol Exp Ther. 2001Feb;296(2):501-9.

REF 8

ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy. Life Sci. 2013 Jul 30;93(2-3):78-88.

REF 9

The effect of GP683, an adenosine kinase inhibitor, on the desflurane anesthetic requirement in dogs. Anesth Analg. 1997 Sep;85(3):675-80.

REF 10

Inhibition of adenosine kinase attenuates interleukin-1- and lipopolysaccharide-induced alterations in articular cartilage metabolism. Osteoarthritis Cartilage. 2005 Mar;13(3):250-7.

REF 11

Crystal structures of human adenosine kinase inhibitor complexes reveal two distinct binding modes. J Med Chem. 2006 Nov 16;49(23):6726-31.

REF 12

Structure-activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase. Bioorg Med Chem. 2010 May 15;18(10):3403-12.

REF 13

Adenosine kinase inhibitor GP515 improves experimental colitis in mice. J Pharmacol Exp Ther. 2001 Jan;296(1):99-105.

REF 14

Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36.

REF 15

Engineered Adenosine-Releasing Cells for Epilepsy Therapy: Human Mesenchymal Stem Cells and Human Embryonic Stem Cells. Neurotherapeutics. 2009 April; 6(2): 278-283.

REF 16

Structure of human adenosine kinase at 1.5 A resolution. Biochemistry. 1998 Nov 10;37(45):15607-20.

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