Target Information

Target General Information

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Target ID

T93344 (Former ID: TTDS00302)

Target Name

Squalene monooxygenase (SQLE)

Synonyms

Squalene epoxidase; SQLE; SE; Oxidosqaulene cyclase

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Gene Name

SQLE

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Dermatophytosis [ICD-11: 1F28]

Skin fungal infection disorder [ICD-11: EA60]

Function

Catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway.

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

ERG1_HUMAN

EC Number

EC 1.14.14.17

Sequence

MWTFLGIATFTYFYKKFGDFITLANREVLLCVLVFLSLGLVLSYRCRHRNGGLLGRQQSG
SQFALFSDILSGLPFIGFFWAKSPPESENKEQLEARRRRKGTNISETSLIGTAACTSTSS
QNDPEVIIVGAGVLGSALAAVLSRDGRKVTVIERDLKEPDRIVGEFLQPGGYHVLKDLGL
GDTVEGLDAQVVNGYMIHDQESKSEVQIPYPLSENNQVQSGRAFHHGRFIMSLRKAAMAE
PNAKFIEGVVLQLLEEDDVVMGVQYKDKETGDIKELHAPLTVVADGLFSKFRKSLVSNKV
SVSSHFVGFLMKNAPQFKANHAELILANPSPVLIYQISSSETRVLVDIRGEMPRNLREYM
VEKIYPQIPDHLKEPFLEATDNSHLRSMPASFLPPSSVKKRGVLLLGDAYNMRHPLTGGG
MTVAFKDIKLWRKLLKGIPDLYDDAAIFEAKKSFYWARKTSHSFVVNILAQALYELFSAT
DDSLHQLRKACFLYFKLGGECVAGPVGLLSVLSPNPLVLIGHFFAVAIYAVYFCFKSEPW
ITKPRALLSSGAVLYKACSVIFPLIYSEMKYMVH

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Naftifine

Drug Info

Approved

Dermatomycosis

[2], [3]

Tolnaftate

Drug Info

Approved

Dermatophytosis

[4]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Epigallocatechin gallate

Drug Info

Phase 3

Hepatic fibrosis

[5], [6], [7], [8]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

FR-194738

Drug Info

Terminated

Hypercholesterolaemia

[9]

SDZ-87-469

Drug Info

Terminated

Coronary artery disease

[10]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 26 Inhibitor drugs

Naftifine

Drug Info

[11], [12]

Tolnaftate

Drug Info

[1], [11]

Epigallocatechin gallate

Drug Info

[13]

NB-598

Drug Info

[15]

1(beta)-O-galloylpedunculagin

Drug Info

[13]

1,2,3,4,6-penta-O-galloyl-beta-D-glucose

Drug Info

[13]

1,2,6-tri-O-galloyl-beta-D-glucose

Drug Info

[13]

Allylamines

Drug Info

[16]

CORILAGIN

Drug Info

[13]

ELLAGIC ACID

Drug Info

[13]

ETHYLGALLATE

Drug Info

[13]

EUGENIIN

Drug Info

[13]

FUROSIN

Drug Info

[13]

GERANIIN

Drug Info

[13]

Green tea

Drug Info

[15]

Mallotinic acid

Drug Info

[13]

Mallotusinic acid

Drug Info

[13]

N-cetylgallate

Drug Info

[13]

OCTYL_GALLATE

Drug Info

[13]

Procyanidin B-2 3,3'-di-O-gallate

Drug Info

[13]

Sanguiin H-6

Drug Info

[13]

Tellurium

Drug Info

[15]

THEASINENSIN A

Drug Info

[13]

Thiocarbamate

Drug Info

[11]

Trisnorsqualene cyclopropylamine

Drug Info

[13]

Trisnorsqualene difluoromethylidene

Drug Info

[13]

Modulator

[+] 2 Modulator drugs

FR-194738

Drug Info

[14]

SDZ-87-469

Drug Info

[1]

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: Flavin-Adenine Dinucleotide

Ligand Info

Structure Description

Human squalene epoxidase (SQLE, squalene monooxygenase) structure with FAD and Cmpd-4"

PDB:6C6N

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

[17]

PDB Sequence

NDPEVIIVGA

¹³¹

GVLGSALAAV

¹⁴¹

LSRDGRKVTV

¹⁵¹

IERDLKEPDR

¹⁶¹

IVGEFLQPGG

¹⁷¹

YHVLKDLGLG

¹⁸¹

DTVEGLDAQV

¹⁹¹

VNGYMIHDQE

²⁰¹

SKSEVQIPYP

²¹¹

LSENNQVQSG

²²¹

RAFHHGRFIM

²³¹

SLRKAAMAEP

²⁴¹

NAKFIEGVVL

²⁵¹

QLLEEDDVVM

²⁶¹

GVQYKDKETG

²⁷¹

DIKELHAPLT

²⁸¹

VVADGLFSKF

²⁹¹

RKSLVSNKVS

³⁰¹

VSSHFVGFLM

³¹¹

KNAPQFKANH

³²¹

AELILANPSP

³³¹

VLIYQISSSE

³⁴¹

TRVLVDIRGE

³⁵¹

MPRNLREYMV

³⁶¹

EKIYPQIPDH

³⁷¹

LKEPFLEATD

³⁸¹

NSHLRSMPAS

³⁹¹

FLPPSSVKKR

⁴⁰¹

GVLLLGDAYN

⁴¹¹

MRHPLTGGGM

⁴²¹

TVAFKDIKLW

⁴³¹

RKLLKGIPDL

⁴⁴¹

YDDAAIFEAK

⁴⁵¹

KSFYWARKTS

⁴⁶¹

HSFVVNILAQ

⁴⁷¹

ALYELFSATD

⁴⁸¹

DSLHQLRKAC

⁴⁹¹

FLYFKLGGEC

⁵⁰¹

VAGPVGLLSV

⁵¹¹

LSPNPLVLIG

⁵²¹

HFFAVAIYAV

⁵³¹

YFCFKSEPWI

⁵⁴¹

TKPRALLSSG

⁵⁵¹

AVLYKACSVI

⁵⁶¹

FPLIYSEMKY

⁵⁷¹

Residue

Distance (Å)

VAL129

4.054

GLY130

3.202

ALA131

3.868

GLY132

3.256

VAL133

3.025

LEU134

2.881

GLY135

4.292

ILE152

3.310

GLU153

2.572

ARG154

2.967

ASP155

4.736

ARG161

2.788

ILE162

4.139

VAL163

3.504

GLY164

3.360

GLU165

3.656

PHE166

2.674

LEU167

4.890

HIS226

4.415

ILE230

4.793

ARG234

3.190

GLY248

3.775

VAL249

3.697

Residue

Distance (Å)

VAL250

3.067

ALA284

3.617

ASP285

3.578

GLY286

3.213

LEU287

4.421

LYS290

4.971

PHE291

4.021

PHE306

3.949

TYR335

4.477

LEU345

4.671

MET388

3.926

PRO389

3.652

LEU406

4.437

GLY407

3.193

ASP408

2.665

ALA409

4.522

ARG413

4.422

PRO415

3.687

GLY418

3.507

GLY419

3.867

GLY420

3.124

MET421

2.842

THR422

4.167

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

Ligand Name: NB-598

Ligand Info

Structure Description

Human squalene epoxidase (SQLE, squalene monooxygenase) structure with FAD and NB-598

PDB:6C6P

Method

X-ray diffraction

Resolution

2.50 Å

Mutation

[17]

PDB Sequence

DPEVIIVGAG

¹³²

VLGSALAAVL

¹⁴²

SRDGRKVTVI

¹⁵²

ERDLKEPDRI

¹⁶²

VGEFLQPGGY

¹⁷²

HVLKDLGLGD

¹⁸²

TVEGLDAQVV

¹⁹²

NGYMIHDQES

²⁰²

KSEVQIPYPL

²¹²

SENNQVQSGR

²²²

AFHHGRFIMS

²³²

LRKAAMAEPN

²⁴²

AKFIEGVVLQ

²⁵²

LLEEDDVVMG

²⁶²

VQYKDKETGD

²⁷²

IKELHAPLTV

²⁸²

VADGLFSKFR

²⁹²

KSLVSNKVSV

³⁰²

SSHFVGFLMK

³¹²

NAPQFKANHA

³²²

ELILANPSPV

³³²

LIYQISSSET

³⁴²

RVLVDIRGEM

³⁵²

PRNLREYMVE

³⁶²

KIYPQIPDHL

³⁷²

KEPFLEATDN

³⁸²

SHLRSMPASF

³⁹²

LPPSSVKKRG

⁴⁰²

VLLLGDAYNM

⁴¹²

RHPLTGGGMT

⁴²²

VAFKDIKLWR

⁴³²

KLLKGIPDLY

⁴⁴²

DDAAIFEAKK

⁴⁵²

SFYWARKTSH

⁴⁶²

SFVVNILAQA

⁴⁷²

LYELFSATDD

⁴⁸²

SLHQLRKACF

⁴⁹²

LYFKLGGECV

⁵⁰²

AGPVGLLSVL

⁵¹²

SPNPLVLIGH

⁵²²

FFAVAIYAVY

⁵³²

FCFKSEPWIT

⁵⁴²

KPRALLSSGA

⁵⁵²

VLYKACSVIF

⁵⁶²

PLIYSEMKY

Residue

Distance (Å)

PHE166

3.391

GLN168

3.897

TYR195

2.693

ILE197

3.600

ILE208

3.645

TYR210

4.104

PHE306

4.766

ALA322

4.384

LEU324

3.832

LEU333

3.453

TYR335

3.209

LEU345

3.875

PRO415

3.056

LEU416

3.240

THR417

3.845

GLY418

3.376

Residue

Distance (Å)

LEU469

3.523

LEU473

3.479

PHE477

3.275

CYS491

4.421

TYR494

4.504

PHE495

3.523

VAL502

4.310

PRO505

3.612

VAL506

3.560

LEU508

4.594

LEU509

3.607

LEU519

3.914

HIS522

3.770

PHE523

3.584

VAL526

3.575

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
Steroid biosynthesis	hsa00100	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy

Degree	12	Degree centrality	1.29E-03	Betweenness centrality	4.11E-05
Closeness centrality	1.98E-01	Radiality	1.34E+01	Clustering coefficient	6.52E-01
Neighborhood connectivity	1.52E+01	Topological coefficient	2.61E-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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 5 KEGG Pathways

Steroid biosynthesis

Sesquiterpenoid and triterpenoid biosynthesis

Metabolic pathways

Biosynthesis of secondary metabolites

Biosynthesis of antibiotics

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Steroid Biosynthesis

Reactome

[+] 2 Reactome Pathways

Cholesterol biosynthesis

Activation of gene expression by SREBF (SREBP)

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Effects of squalene epoxidase inhibitors on Candida albicans. Antimicrob Agents Chemother. 1992 Aug;36(8):1779-81.

REF 2

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 019356.

REF 3

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

REF 4

Drug information of Tolnaftate, 2008. eduDrugs.

REF 5

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: 7002).

REF 6

The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a beta-secretase inhibitor. Bioorg Med Chem Lett. 2012 Feb 1;22(3):1408-14.

REF 7

Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss-Webster mouse. Toxicol Sci. 2003 Dec;76(2):262-70.

REF 8

Prolyl endopeptidase inhibitors from green tea. Arch Pharm Res. 2001 Aug;24(4):292-6.

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009590)

REF 10

Chemotherapy of fungal diseases. 1990. Page(525-550).

REF 11

Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents. Antimicrob Agents Chemother. 1996 Feb;40(2):443-7.

REF 12

Mode of action of anti-Candida drugs: focus on terconazole and other ergosterol biosynthesis inhibitors. Am J Obstet Gynecol. 1991 Oct;165(4 Pt 2):1193-9.

REF 13

Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase. J Nat Prod. 2001 Aug;64(8):1010-4.

REF 14

Synthesis and biological activity of a novel squalene epoxidase inhibitor, FR194738. Bioorg Med Chem Lett. 2004 Feb 9;14(3):633-7.

REF 15

Squalene epoxidase as hypocholesterolemic drug target revisited. Prog Lipid Res. 2003 Jan;42(1):37-50.

REF 16

Differential inhibition of fungal amd mammalian squalene epoxidases by the benzylamine SDZ SBA 586 in comparison with the allylamine terbinafine. Arch Biochem Biophys. 1997 Apr 15;340(2):265-9.

REF 17

Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase. Nat Commun. 2019 Jan 9;10(1):97.

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