Target Information
| Target General Information | Top | |||||
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| Target ID |
T68706
(Former ID: TTDI02227)
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| Target Name |
Dibasic-processing enzyme (Furin)
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| Synonyms |
Paired basic amino acid residuecleaving enzyme; Paired basic amino acid residue-cleaving enzyme; PCSK3; PACE; FUR; Dibasicprocessing enzyme
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| Gene Name |
FURIN
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Coronavirus infection [ICD-11: 1D92] | |||||
| Function |
Mediates processing of TGFB1, an essential step in TGF-beta-1 activation. Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.75
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| Sequence |
MELRPWLLWVVAATGTLVLLAADAQGQKVFTNTWAVRIPGGPAVANSVARKHGFLNLGQI
FGDYYHFWHRGVTKRSLSPHRPRHSRLQREPQVQWLEQQVAKRRTKRDVYQEPTDPKFPQ QWYLSGVTQRDLNVKAAWAQGYTGHGIVVSILDDGIEKNHPDLAGNYDPGASFDVNDQDP DPQPRYTQMNDNRHGTRCAGEVAAVANNGVCGVGVAYNARIGGVRMLDGEVTDAVEARSL GLNPNHIHIYSASWGPEDDGKTVDGPARLAEEAFFRGVSQGRGGLGSIFVWASGNGGREH DSCNCDGYTNSIYTLSISSATQFGNVPWYSEACSSTLATTYSSGNQNEKQIVTTDLRQKC TESHTGTSASAPLAAGIIALTLEANKNLTWRDMQHLVVQTSKPAHLNANDWATNGVGRKV SHSYGYGLLDAGAMVALAQNWTTVAPQRKCIIDILTEPKDIGKRLEVRKTVTACLGEPNH ITRLEHAQARLTLSYNRRGDLAIHLVSPMGTRSTLLAARPHDYSADGFNDWAFMTTHSWD EDPSGEWVLEIENTSEANNYGTLTKFTLVLYGTAPEGLPVPPESSGCKTLTSSQACVVCE EGFSLHQKSCVQHCPPGFAPQVLDTHYSTENDVETIRASVCAPCHASCATCQGPALTDCL SCPSHASLDPVEQTCSRQSQSSRESPPQQQPPRLPPEVEAGQRLRAGLLPSHLPEVVAGL SCAFIVLVFVTVFLVLQLRSGFSFRGVKVYTMDRGLISYKGLPPEAWQEECPSDSEEDEG RGERTAFIKDQSAL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T88M4K | |||||
| 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: (1-{[2-(3,5-Dichlorophenyl)-6-{[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxy}pyridin-4-yl]methyl}piperidin-4-yl)acetic acid | Ligand Info | |||||
| Structure Description | X-ray structure of Furin bound to BOS-318, a small molecule inhibitor | PDB:7LCU | ||||
| Method | X-ray diffraction | Resolution | 1.24 Å | Mutation | No | [6] |
| PDB Sequence |
YQEPTDPKFP
119 QQWYLSGVTQ129 RDLNVKAAWA139 QGYTGHGIVV149 SILDDGIEKN159 HPDLAGNYDP 169 GASFDVNDQD179 PDPQPRYTQM189 NDNRHGTRCA199 GEVAAVANNG209 VCGVGVAYNA 219 RIGGVRMLDG229 EVTDAVEARS239 LGLNPNHIHI249 YSASWGPEDD259 GKTVDGPARL 269 AEEAFFRGVS279 QGRGGLGSIF289 VWASGNGGRE299 HDSCNCDGYT309 NSIYTLSISS 319 ATQFGNVPWY329 SEACSSTLAT339 TYSSGNQNEK349 QIVTTDLRQK359 CTESHTGTSA 369 SAPLAAGIIA379 LTLEANKDLT389 WRDMQHLVVQ399 TSKPAHLNAN409 DWATNGVGRK 419 VSHSYGYGLL429 DAGAMVALAQ439 DWTTVAPQRK449 CIIDILTEPK459 DIGKRLEVRK 469 TVTACLGEPN479 HITRLEHAQA489 RLTLSYNRRG499 DLAIHLVSPM509 GTRSTLLAAR 519 PHDYSADGFN529 DWAFMTTHSW539 DEDPSGEWVL549 EIENTSEANN559 YGTLTKFTLV 569 LYGTAGENLY579
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LEU152
3.171
ASP153
4.470
ASP154
4.801
ASP191
3.520
HIS194
2.767
MET226
3.530
LEU227
3.274
VAL231
2.757
THR232
3.411
ASP233
2.827
GLU236
2.615
LEU240
3.700
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| Ligand Name: 1-[(1R,2R,4S,5S)-2,4-bis(4-carbamimidamidophenoxy)-5-[(4-carbamimidamidophenyl)amino]cyclohexyl]guanidine | Ligand Info | |||||
| Structure Description | Xray structure of human furin bound with the 2,5-dideoxystreptamine derived small molecule inhibitor 1n | PDB:5MIM | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [7] |
| PDB Sequence |
VYQEPTDPKF
118 PQQWYLSGVT128 QRDLNVKAAW138 AQGYTGHGIV148 VSILDDGIEK158 NHPDLAGNYD 168 PGASFDVNDQ178 DPDPQPRYTQ188 MNDNRHGTRC198 AGEVAAVANN208 GVCGVGVAYN 218 ARIGGVRMLD228 GEVTDAVEAR238 SLGLNPNHIH248 IYSASWGPED258 DGKTVDGPAR 268 LAEEAFFRGV278 SQGRGGLGSI288 FVWASGNGGR298 EHDSCNCDGY308 TNSIYTLSIS 318 SATQFGNVPW328 YSEACSSTLA338 TTYSSGNQNE348 KQIVTTDLRQ358 KCTESHTGTS 368 ASAPLAAGII378 ALTLEANKNL388 TWRDMQHLVV398 QTSKPAHLNA408 NDWATNGVGR 418 KVSHSYGYGL428 LDAGAMVALA438 QNWTTVAPQR448 KCIIDILTEP458 KDIGKRLEVR 468 KTVTACLGEP478 NHITRLEHAQ488 ARLTLSYNRR498 GDLAIHLVSP508 MGTRSTLLAA 518 RPHDYSADGF528 NDWAFMTTHS538 WDEDPSGEWV548 LEIENTSEAN558 NYGTLTKFTL 568 VLYGTASGSL578 VPR
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ASP153
2.922
ASP154
3.728
ASP177
4.923
ARG185
3.526
ASP191
3.378
ASN192
2.886
HIS194
3.353
CYS198
3.619
ARG225
4.027
LEU227
3.580
ASP228
3.180
GLY229
3.218
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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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Extracellular matrix organizing protein FRAS1 (FRAS1) | 30.986 (22/71) | 3.00E-03 |
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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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| Viral life cycle - HIV-1 | hsa03250 | Affiliated Target |
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| Class: Genetic Information Processing => Information processing in viruses | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 6.51E-04 |
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| Closeness centrality | 2.07E-01 | Radiality | 1.36E+01 | Clustering coefficient | 3.57E-02 |
| Neighborhood connectivity | 1.19E+01 | Topological coefficient | 1.36E-01 | Eccentricity | 12 |
| 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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating Transcription Factors | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| Panther Pathway | [+] 3 Panther Pathways | + | ||||
| 1 | Alzheimer disease-amyloid secretase pathway | |||||
| 2 | Alzheimer disease-presenilin pathway | |||||
| 3 | Endothelin signaling pathway | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | Notch signaling pathway | |||||
| 2 | p75(NTR)-mediated signaling | |||||
| 3 | HIF-1-alpha transcription factor network | |||||
| 4 | Glypican 3 network | |||||
| References | Top | |||||
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| REF 1 | Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor. J Med Chem. 2014 Jan 9;57(1):98-109. | |||||
| REF 2 | Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47. | |||||
| REF 3 | Inhibitors of Furin and other pro-protein convertases. US9266828. | |||||
| REF 4 | Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J Biol Chem. 2007 Jul 20;282(29):20847-53. | |||||
| REF 5 | Novel Furin Inhibitors with Potent Anti-infectious Activity. ChemMedChem. 2015 Jul;10(7):1218-31. | |||||
| REF 6 | A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease. Cell Chem Biol. 2022 Jun 16;29(6):947-957.e8. | |||||
| REF 7 | Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor. ACS Chem Biol. 2017 May 19;12(5):1211-1216. | |||||
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