Target Information

Target General Information

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Target ID

T11843 (Former ID: TTDS00398)

Target Name

Vitamin K epoxide reductase complex 1 (VKORC1)

Synonyms

Vitamin K1 2,3-epoxide reductase subunit 1; VKORC1; VKOR; UNQ308/PRO351; MSTP576; MSTP134

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Gene Name

VKORC1

Target Type

Successful target

[1]

Disease

[+] 5 Target-related Diseases

Bleeding disorder [ICD-11: GA20-GA21]

Coagulation defect [ICD-11: 3B10]

Pulmonary thromboembolism [ICD-11: BB00]

Supraventricular tachyarrhythmia [ICD-11: BC81]

Thrombosis [ICD-11: DB61-GB90]

Function

Involved invitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.

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BioChemical Class

Short-chain dehydrogenases reductase

UniProt ID

VKOR1_HUMAN

EC Number

EC 1.17.4.4

Sequence

MGSTWGSPGWVRLALCLTGLVLSLYALHVKAARARDRDYRALCDVGTAISCSRVFSSRWG
RGFGLVEHVLGQDSILNQSNSIFGCIFYTLQLLLGCLRTRWASVLMLLSSLVSLAGSVYL
AWILFFVLYDFCIVCITTYAINVSLMWLSFRKVQEPQGKAKRH

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 5 Approved Drugs

Acenocoumarol

Drug Info

Approved

Thrombosis

[2]

Dicumarol

Drug Info

Approved

Thrombosis

[3], [4], [5]

Phenindione

Drug Info

Approved

Coagulation defect

[5], [6], [7]

Phenprocoumon

Drug Info

Approved

Thrombosis

[5], [8], [9]

Warfarin

Drug Info

Approved

Atrial fibrillation

[10], [11]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Tecarfarin

Drug Info

Phase 3

Cerebrovascular ischaemia

[12]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 6 Inhibitor drugs

Acenocoumarol

Drug Info

[13], [14], [15]

Dicumarol

Drug Info

[1]

Phenindione

Drug Info

[15]

Phenprocoumon

Drug Info

[15]

Warfarin

Drug Info

[15]

Tecarfarin

Drug Info

[16]

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: Warfarin

Ligand Info

Structure Description

Human VKOR with warfarin

PDB:6WV3

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

Yes

[17]

PDB Sequence

KGEELFTGVV

¹²

PILVELDGDV

²²

NGHKFSVRGE

³²

GEGDATNGKL

⁴²

TLKFICTTGK

⁵²

LPVPWPTLVT

⁶²

TLVQCFSRYP

⁷⁵

DHMKRHDFFK

⁸⁵

SAMPEGYVQE

⁹⁵

RTISFKDDGT

¹⁰⁵

YKTRAEVKFE

¹¹⁵

GDTLVNRIEL

¹²⁵

KGIDFKEDGN

¹³⁵

ILGHKLEYNS

¹⁴⁵

TWGSPGWVRL

¹⁵⁵

ALCLTGLVLS

¹⁶⁵

LYALHVKAAR

¹⁷⁵

ARDRDYRALC

¹⁸⁵

DVGTAISCSR

¹⁹⁵

VFSSRWGRGF

²⁰⁵

GLVEHVLGQD

²¹⁵

SILNQSNSIF

²²⁵

GCIFYTLQLL

²³⁵

LGCLRTRWAS

²⁴⁵

VLMLLSSLVS

²⁵⁵

LAGSVYLAWI

²⁶⁵

LFFVLYDFCI

²⁷⁵

VCITTYAINV

²⁸⁵

SLMWLSFRKV

²⁹⁵

QENSHNVYIT

³⁰⁵

ADKQKNGIKA

³¹⁵

NFKIRHNVED

³²⁵

GSVQLADHYQ

³³⁵

QNTPIGDGPV

³⁴⁵

LLPDNHYLST

³⁵⁵

QSVLSKDPNE

³⁶⁵

KRDHMVLLEF

³⁷⁵

VTAAGITHHH

³⁸⁵

Residue

Distance (Å)

LEU164

4.218

SER165

4.752

ALA168

3.667

VAL196

3.542

PHE197

3.701

SER199

3.864

TRP201

3.714

GLY202

3.730

PHE205

3.760

ASN222

2.762

SER223

3.938

Residue

Distance (Å)

SER259

3.584

LEU262

3.207

ALA263

4.972

ILE265

3.761

LEU266

3.746

LEU270

3.708

VAL276

3.320

CYS277

3.409

THR280

3.107

TYR281

2.462

ASN284

3.967

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Phenindione

Ligand Info

Structure Description

Human VKOR with phenindione

PDB:6WV6

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

Yes

[17]

PDB Sequence

SKGEELFTGV

¹¹

VPILVELDGD

²¹

VNGHKFSVRG

³¹

EGEGDATNGK

⁴¹

LTLKFICTTG

⁵¹

KLPVPWPTLV

⁶¹

TTLVQCFSRY

⁷⁴

PDHMKRHDFF

⁸⁴

KSAMPEGYVQ

⁹⁴

ERTISFKDDG

¹⁰⁴

TYKTRAEVKF

¹¹⁴

EGDTLVNRIE

¹²⁴

LKGIDFKEDG

¹³⁴

NILGHKLEYN

¹⁴⁴

STWGSPGWVR

¹⁵⁴

LALCLTGLVL

¹⁶⁴

SLYALHVKAA

¹⁷⁴

RARDRDYRAL

¹⁸⁴

CDVGTAISCS

¹⁹⁴

RVFSSRWGRG

²⁰⁴

FGLVEHVLGQ

²¹⁴

DSILNQSNSI

²²⁴

FGCIFYTLQL

²³⁴

LLGCLRTRWA

²⁴⁴

SVLMLLSSLV

²⁵⁴

SLAGSVYLAW

²⁶⁴

ILFFVLYDFC

²⁷⁴

IVCITTYAIN

²⁸⁴

VSLMWLSFRK

²⁹⁴

VQENSHNVYI

³⁰⁴

TADKQKNGIK

³¹⁴

ANFKIRHNVE

³²⁴

DGSVQLADHY

³³⁴

QQNTPIGDGP

³⁴⁴

VLLPDNHYLS

³⁵⁴

TQSVLSKDPN

³⁶⁴

EKRDHMVLLE

³⁷⁴

FVTAAGITHH

³⁸⁴

Residue

Distance (Å)

LEU164

4.012

SER165

3.421

ALA168

3.682

VAL196

2.946

PHE197

2.643

SER199

3.701

TRP201

3.432

GLY202

3.449

ASN222

2.990

SER223

2.886

Residue

Distance (Å)

LEU262

2.972

ALA263

4.392

ILE265

3.357

LEU266

3.156

LEU270

3.623

CYS274

4.572

VAL276

3.681

CYS277

3.054

THR280

2.519

TYR281

2.484

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
Ubiquinone and other terpenoid-quinone biosynthesis	hsa00130	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.51E-01	Radiality	1.20E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	9.00E+00	Topological coefficient	1.00E+00	Eccentricity	14
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

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 Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Ubiquinone and other terpenoid-quinone biosynthesis

Pathwhiz Pathway

[+] 2 Pathwhiz Pathways

Vitamin K Metabolism

Coagulation

WikiPathways

[+] 1 WikiPathways

PTM: gamma carboxylation, hypusine formation and arylsulfatase activation

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Vitamin K antagonism of coumarin intoxication in the rat. Thromb Haemost. 1986 Apr 30;55(2):235-9.

REF 2

Drug information of Acenocoumarol, 2008. eduDrugs.

REF 3

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: 6808).

REF 4

Drug information of Dicumarol, 2008. eduDrugs.

REF 5

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

REF 6

REF 7

Drug information of Phenindione, 2008. eduDrugs.

REF 8

REF 9

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 011228.

REF 10

REF 11

Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90.

REF 12

ClinicalTrials.gov (NCT02522221) Tecarfarin Anti-Coagulation Trial (TACT).

REF 13

Evaluation of a reverse-hybridization StripAssay for the detection of genetic polymorphisms leading to acenocoumarol sensitivity. Mol Biol Rep. 2010 Apr;37(4):1693-7.

REF 14

Genotypes associated with reduced activity of VKORC1 and CYP2C9 and their modification of acenocoumarol anticoagulation during the initial treatmen... Clin Pharmacol Ther. 2009 Apr;85(4):379-86.

REF 15

[Oral anticoagulation and pharmacogenetics: importance in the clinical setting]. Rev Med Suisse. 2007 Sep 12;3(124):2030, 2033-4, 2036.

REF 16

Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants. J Clin Pharmacol. 2011Apr;51(4):561-74.

REF 17

Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation. Science. 2021 Jan 1;371(6524):eabc5667.

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