Target Information

Target General Information

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Target ID

T98933 (Former ID: TTDR01227)

Target Name

Thyroid hormone receptor beta (THRB)

Synonyms

c-erbA-beta; c-erbA-2; THR1; Nuclear receptor subfamily 1 group A member 2; NR1A2; ERBA2

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Gene Name

THRB

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Hyper-lipoproteinaemia [ICD-11: 5C80]

Function

High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. Nuclear hormone receptor that can act as a repressor or activator of transcription.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

THB_HUMAN

Sequence

MTPNSMTENGLTAWDKPKHCPDREHDWKLVGMSEACLHRKSHSERRSTLKNEQSSPHLIQ
TTWTSSIFHLDHDDVNDQSVSSAQTFQTEEKKCKGYIPSYLDKDELCVVCGDKATGYHYR
CITCEGCKGFFRRTIQKNLHPSYSCKYEGKCVIDKVTRNQCQECRFKKCIYVGMATDLVL
DDSKRLAKRKLIEENREKRRREELQKSIGHKPEPTDEEWELIKTVTEAHVATNAQGSHWK
QKRKFLPEDIGQAPIVNAPEGGKVDLEAFSHFTKIITPAITRVVDFAKKLPMFCELPCED
QIILLKGCCMEIMSLRAAVRYDPESETLTLNGEMAVTRGQLKNGGLGVVSDAIFDLGMSL
SSFNLDDTEVALLQAVLLMSSDRPGLACVERIEKYQDSFLLAFEHYINYRKHHVTHFWPK
LLMKVTDLRMIGACHASRFLHMKVECPTELFPPLFLEVFED

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3D Structure

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AlphaFold

HIT2.0 ID

T12PPL

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Dextrothyroxine Sodium

Drug Info

Approved

High blood cholesterol level

[2]

Clinical Trial Drug(s)

[+] 6 Clinical Trial Drugs

BCT303

Drug Info

Phase 2

Hypothyroidism

[3]

MB-07811

Drug Info

Phase 2

Hyperlipidaemia

[4]

MGL-3196

Drug Info

Phase 2

Familial hypercholesterolemia

[5]

VK-2809

Drug Info

Phase 2

Hypercholesterolaemia

[5]

ZYT-1

Drug Info

Phase 1

Lipid metabolism disorder

[8]

tiratricol

Drug Info

Clinical trial

Wound healing

[9]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 4 Modulator drugs

Dextrothyroxine Sodium

Drug Info

[1]

BCT303

Drug Info

[10]

MB-07811

Drug Info

[11]

ZYT-1

Drug Info

[10]

Agonist

[+] 4 Agonist drugs

MGL-3196

Drug Info

[12]

VK-2809

Drug Info

[5]

tiratricol

Drug Info

[13]

rT3

Drug Info

[13]

Inhibitor

[+] 22 Inhibitor drugs

(3,5-Dibromo-4-butoxy-phenyl)-acetic acid

Drug Info

[14]

(3,5-Dibromo-4-hexyloxy-phenyl)-acetic acid

Drug Info

[14]

(3,5-Dibromo-4-pentyloxy-phenyl)-acetic acid

Drug Info

[14]

(4-hexylphenyl)(oxiran-2-yl)methanone

Drug Info

[15]

(E)-1-(4-heptylphenyl)but-2-en-1-one

Drug Info

[15]

(Z)-4-(4-hexylphenylamino)-4-oxobut-2-enoic acid

Drug Info

[15]

1-(4-(Hexyloxy)phenyl)-3-morpholinopropan-1-one

Drug Info

[16]

1-(4-heptylphenyl)prop-2-en-1-one

Drug Info

[15]

1-(4-hexylphenyl)-3-(propylamino)propan-1-one

Drug Info

[15]

1-(4-hexylphenyl)-3-morpholinopropan-1-one

Drug Info

[15]

2-hexylphenyl acrylate

Drug Info

[15]

3-(3,5-Dibromo-4-hexyloxy-phenyl)-propionic acid

Drug Info

[14]

3-(4-(benzyloxy)-3,5-dibromophenyl)propanoic acid

Drug Info

[17]

3-(dibutylamino)-1-(4-hexylphenyl)propan-1-one

Drug Info

[15]

3-(dimethylamino)-1-(4-heptylphenyl)propan-1-one

Drug Info

[16]

3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one

Drug Info

[15]

3-bromo-1-(4-hexylphenyl)propan-1-one

Drug Info

[15]

4-(3-(Dimethylamino)propanoyl)-N-hexylbenzamide

Drug Info

[16]

4-(4-hexylphenyl)-4-oxobut-2-enoic acid

Drug Info

[15]

Cacodylate Ion

Drug Info

[18]

Detrothyronine

Drug Info

[19]

GC-24

Drug Info

[18]

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: Levothyroxine

Ligand Info

Structure Description

Thyroxine-Thyroid Hormone Receptor Interactions

PDB:1Y0X

Method

X-ray diffraction

Resolution

3.10 Å

Mutation

[20]

PDB Sequence

SHMEELQKSI

²⁰⁸

GHKPEPTDEE

²¹⁸

WELIKTVTEA

²²⁸

HVATNAQGSH

²³⁸

WKQKRKFLPE

²⁴⁸

DIGVDLEAFS

²⁷⁰

HFTKIITPAI

²⁸⁰

TRVVDFAKKL

²⁹⁰

PMFCELPCED

³⁰⁰

QIILLKGCCM

³¹⁰

EIMSLRAAVR

³²⁰

YDPESETLTL

³³⁰

NGEMAVTRGQ

³⁴⁰

LKNGGLGVVS

³⁵⁰

DAIFDLGMSL

³⁶⁰

SSFNLDDTEV

³⁷⁰

ALLQAVLLMS

³⁸⁰

SDRPGLACVE

³⁹⁰

RIEKYQDSFL

⁴⁰⁰

LAFEHYINYR

⁴¹⁰

KHHVTHFWPK

⁴²⁰

LLMKVTDLRM

⁴³⁰

IGACHASRFL

⁴⁴⁰

HMKVECPTEL

⁴⁵⁰

FPPLFLEVFE

⁴⁶⁰

Residue

Distance (Å)

ASN233

4.827

PHE269

4.184

PHE272

3.217

ILE275

3.709

ILE276

3.646

ALA279

3.544

ARG282

2.861

MET310

3.654

MET313

3.117

SER314

3.985

ARG316

3.510

ALA317

3.836

ARG320

3.939

Residue

Distance (Å)

THR329

3.840

LEU330

3.495

ASN331

3.116

GLY332

4.242

LEU341

4.022

GLY344

3.963

GLY345

4.386

LEU346

3.635

ILE353

3.392

HIS435

3.182

MET442

3.574

PHE455

3.041

PHE459

3.543

Ligand Name: Liothyronine

Ligand Info

Structure Description

Crystal Structure of T3-Bound Thyroid Hormone Receptor

PDB:3GWS

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[21]

PDB Sequence

EELQKSIGHK

²¹¹

PEPTDEEWEL

²²¹

IKTVTEAHVA

²³¹

TNAQGSHWKQ

²⁴¹

KRKFLPEDIG

²⁵¹

VDLEAFSHFT

²⁷³

KIITPAITRV

²⁸³

VDFAKKLPMF

²⁹³

ELPCEDQIIL

³⁰⁴

LKGCCMEIMS

³¹⁴

LRAAVRYDPE

³²⁴

SETLTLNGEM

³³⁴

AVTRGQLKNG

³⁴⁴

GLGVVSDAIF

³⁵⁴

DLGMSLSSFN

³⁶⁴

LDDTEVALLQ

³⁷⁴

AVLLMSSDRP

³⁸⁴

GLAVERIEKY

³⁹⁵

QDSFLLAFEH

⁴⁰⁵

YINYRKHHVT

⁴¹⁵

HFWPKLLMKV

⁴²⁵

TDLRMIGAHA

⁴³⁶

SRFLHMKVEC

⁴⁴⁶

PTELFPPLFL

⁴⁵⁶

EVFE

Residue

Distance (Å)

ASN233

4.813

ALA234

4.865

PHE269

4.159

PHE272

3.101

THR273

4.727

ILE275

3.859

ILE276

3.502

ALA279

3.534

ARG282

2.675

MET310

3.728

MET313

3.380

SER314

4.322

ARG316

3.516

ALA317

3.842

Residue

Distance (Å)

ARG320

4.052

THR329

3.635

LEU330

3.308

ASN331

3.123

GLY332

4.533

LEU341

4.014

GLY344

3.608

GLY345

4.392

LEU346

3.590

ILE353

3.488

HIS435

2.732

MET442

4.040

PHE455

3.545

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

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

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

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
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Thyroid hormone signaling pathway	hsa04919	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	7	Degree centrality	7.52E-04	Betweenness centrality	8.87E-06
Closeness centrality	2.22E-01	Radiality	1.39E+01	Clustering coefficient	5.24E-01
Neighborhood connectivity	3.96E+01	Topological coefficient	2.35E-01	Eccentricity	11
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 Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Thyroid hormone signaling pathway

PID Pathway

[+] 1 PID Pathways

RXR and RAR heterodimerization with other nuclear receptor

Reactome

[+] 1 Reactome Pathways

Nuclear Receptor transcription pathway

WikiPathways

[+] 3 WikiPathways

SIDS Susceptibility Pathways

Hematopoietic Stem Cell Differentiation

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

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

REF 2

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

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 800037654)

REF 4

ClinicalTrials.gov (NCT00879112) Study of MB07811 in Subjects With Hypercholesterolemia. U.S. National Institutes of Health.

REF 5

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

Bacterial biosensors for screening isoform-selective ligands for human thyroid receptors alpha-1 and beta-1. FEBS Open Bio. 2012; 2: 247-253.

REF 7

ClinicalTrials.gov (NCT04973657) Phase 1b, Multi-center, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety, Tolerability, PD and PK of VK0214, in Subjects With the Adrenomyeloneuropathy Form (AMN) of X-linked Adrenoleukodystrophy (X-ALD). U.S.National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT01543269) A Clinical Study to Evaluate the Safety,Tolerability and PK of ZYT1, Following Oral Administration in Healthy Volunteers. U.S. National Institutes of Health.

REF 9

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: 2637).

REF 10

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 11

REF 12

Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis. 2013 Oct;230(2):373-80.

REF 13

Binding of 3,5,3'-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol. 1990 Feb;4(2):227-34.

REF 14

Thyroid receptor ligands. 3. Design and synthesis of 3,5-dihalo-4-alkoxyphenylalkanoic acids as indirect antagonists of the thyroid hormone receptor. J Med Chem. 2005 May 5;48(9):3114-7.

REF 15

Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships. J Med Chem. 2007 Nov 1;50(22):5269-80.

REF 16

Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors. J Med Chem. 2009 Jul 9;52(13):3892-901.

REF 17

Thyroid receptor ligands. Part 7: Indirect antagonists of the thyroid hormone receptor with improved affinity. Bioorg Med Chem Lett. 2007 Apr 1;17(7):2018-21.

REF 18

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 19

Thyroid receptor ligands. Part 5: novel bicyclic agonist ligands selective for the thyroid hormone receptor beta. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1240-4.

REF 20

Thyroxine-thyroid hormone receptor interactions. J Biol Chem. 2004 Dec 31;279(53):55801-8.

REF 21

Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. J Mol Biol. 2006 Jul 14;360(3):586-98.

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