Target Information
Target General Information | Top | |||||
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Target ID |
T93344
(Former ID: TTDS00302)
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Target Name |
Squalene monooxygenase (SQLE)
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Synonyms |
Squalene epoxidase; SQLE; SE; Oxidosqaulene cyclase
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Gene Name |
SQLE
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Dermatophytosis [ICD-11: 1F28] | |||||
2 | 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
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UniProt ID | ||||||
EC Number |
EC 1.14.14.17
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Sequence |
MWTFLGIATFTYFYKKFGDFITLANREVLLCVLVFLSLGLVLSYRCRHRNGGLLGRQQSG
SQFALFSDILSGLPFIGFFWAKSPPESENKEQLEARRRRKGTNISETSLIGTAACTSTSS QNDPEVIIVGAGVLGSALAAVLSRDGRKVTVIERDLKEPDRIVGEFLQPGGYHVLKDLGL GDTVEGLDAQVVNGYMIHDQESKSEVQIPYPLSENNQVQSGRAFHHGRFIMSLRKAAMAE PNAKFIEGVVLQLLEEDDVVMGVQYKDKETGDIKELHAPLTVVADGLFSKFRKSLVSNKV SVSSHFVGFLMKNAPQFKANHAELILANPSPVLIYQISSSETRVLVDIRGEMPRNLREYM VEKIYPQIPDHLKEPFLEATDNSHLRSMPASFLPPSSVKKRGVLLLGDAYNMRHPLTGGG MTVAFKDIKLWRKLLKGIPDLYDDAAIFEAKKSFYWARKTSHSFVVNILAQALYELFSAT DDSLHQLRKACFLYFKLGGECVAGPVGLLSVLSPNPLVLIGHFFAVAIYAVYFCFKSEPW ITKPRALLSSGAVLYKACSVIFPLIYSEMKYMVH Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
1 | Naftifine | Drug Info | Approved | Dermatomycosis | [2], [3] | |
2 | Tolnaftate | Drug Info | Approved | Dermatophytosis | [4] | |
Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | Epigallocatechin gallate | Drug Info | Phase 3 | Hepatic fibrosis | [5], [6], [7], [8] | |
Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
1 | FR-194738 | Drug Info | Terminated | Hypercholesterolaemia | [9] | |
2 | SDZ-87-469 | Drug Info | Terminated | Coronary artery disease | [10] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 30 Inhibitor drugs | + | ||||
1 | Naftifine | Drug Info | [11], [12] | |||
2 | Tolnaftate | Drug Info | [1], [11] | |||
3 | Epigallocatechin gallate | Drug Info | [13] | |||
4 | NB-598 | Drug Info | [15] | |||
5 | 1(beta)-O-galloylpedunculagin | Drug Info | [13] | |||
6 | 1,2,3,4,6-penta-O-galloyl-beta-D-glucose | Drug Info | [13] | |||
7 | 1,2,6-tri-O-galloyl-beta-D-glucose | Drug Info | [13] | |||
8 | Allylamines | Drug Info | [16] | |||
9 | Chebulinic acid | Drug Info | [13] | |||
10 | CORILAGIN | Drug Info | [13] | |||
11 | ELLAGIC ACID | Drug Info | [13] | |||
12 | ETHYLGALLATE | Drug Info | [13] | |||
13 | EUGENIIN | Drug Info | [13] | |||
14 | FUROSIN | Drug Info | [13] | |||
15 | GERANIIN | Drug Info | [13] | |||
16 | Green tea | Drug Info | [15] | |||
17 | Mallotinic acid | Drug Info | [13] | |||
18 | Mallotusinic acid | Drug Info | [13] | |||
19 | N-cetylgallate | Drug Info | [13] | |||
20 | N-dodecylgallate | Drug Info | [13] | |||
21 | OCTYL_GALLATE | Drug Info | [13] | |||
22 | Pedunculagin | Drug Info | [13] | |||
23 | Procyanidin B-2 3,3'-di-O-gallate | Drug Info | [13] | |||
24 | Sanguiin H-6 | Drug Info | [13] | |||
25 | Tellurium | Drug Info | [15] | |||
26 | THEASINENSIN A | Drug Info | [13] | |||
27 | Thiocarbamate | Drug Info | [11] | |||
28 | Trisnorsqualene alcohol | Drug Info | [13] | |||
29 | Trisnorsqualene cyclopropylamine | Drug Info | [13] | |||
30 | Trisnorsqualene difluoromethylidene | Drug Info | [13] | |||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | FR-194738 | Drug Info | [14] | |||
2 | SDZ-87-469 | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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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 | No | [17] |
PDB Sequence |
NDPEVIIVGA
131 GVLGSALAAV141 LSRDGRKVTV151 IERDLKEPDR161 IVGEFLQPGG171 YHVLKDLGLG 181 DTVEGLDAQV191 VNGYMIHDQE201 SKSEVQIPYP211 LSENNQVQSG221 RAFHHGRFIM 231 SLRKAAMAEP241 NAKFIEGVVL251 QLLEEDDVVM261 GVQYKDKETG271 DIKELHAPLT 281 VVADGLFSKF291 RKSLVSNKVS301 VSSHFVGFLM311 KNAPQFKANH321 AELILANPSP 331 VLIYQISSSE341 TRVLVDIRGE351 MPRNLREYMV361 EKIYPQIPDH371 LKEPFLEATD 381 NSHLRSMPAS391 FLPPSSVKKR401 GVLLLGDAYN411 MRHPLTGGGM421 TVAFKDIKLW 431 RKLLKGIPDL441 YDDAAIFEAK451 KSFYWARKTS461 HSFVVNILAQ471 ALYELFSATD 481 DSLHQLRKAC491 FLYFKLGGEC501 VAGPVGLLSV511 LSPNPLVLIG521 HFFAVAIYAV 531 YFCFKSEPWI541 TKPRALLSSG551 AVLYKACSVI561 FPLIYSEMKY571 |
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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
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
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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 | No | [17] |
PDB Sequence |
DPEVIIVGAG
132 VLGSALAAVL142 SRDGRKVTVI152 ERDLKEPDRI162 VGEFLQPGGY172 HVLKDLGLGD 182 TVEGLDAQVV192 NGYMIHDQES202 KSEVQIPYPL212 SENNQVQSGR222 AFHHGRFIMS 232 LRKAAMAEPN242 AKFIEGVVLQ252 LLEEDDVVMG262 VQYKDKETGD272 IKELHAPLTV 282 VADGLFSKFR292 KSLVSNKVSV302 SSHFVGFLMK312 NAPQFKANHA322 ELILANPSPV 332 LIYQISSSET342 RVLVDIRGEM352 PRNLREYMVE362 KIYPQIPDHL372 KEPFLEATDN 382 SHLRSMPASF392 LPPSSVKKRG402 VLLLGDAYNM412 RHPLTGGGMT422 VAFKDIKLWR 432 KLLKGIPDLY442 DDAAIFEAKK452 SFYWARKTSH462 SFVVNILAQA472 LYELFSATDD 482 SLHQLRKACF492 LYFKLGGECV502 AGPVGLLSVL512 SPNPLVLIGH522 FFAVAIYAVY 532 FCFKSEPWIT542 KPRALLSSGA552 VLYKACSVIF562 PLIYSEMKY
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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
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Steroid biosynthesis | hsa00100 | Affiliated Target |
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Class: Metabolism => Lipid metabolism | Pathway Hierarchy |
Degree | 12 | Degree centrality | 1.29E-03 | Betweenness centrality | 4.11E-05 |
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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 | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) | ||||||
Drug Resistance Mutation (DRM) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
1 | Steroid biosynthesis | |||||
2 | Sesquiterpenoid and triterpenoid biosynthesis | |||||
3 | Metabolic pathways | |||||
4 | Biosynthesis of secondary metabolites | |||||
5 | Biosynthesis of antibiotics | |||||
Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
1 | Steroid Biosynthesis | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | Cholesterol biosynthesis | |||||
2 | Activation of gene expression by SREBF (SREBP) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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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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