Target Information
| Target General Information | Top | |||||
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| Target ID |
T31992
(Former ID: TTDR00213)
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| Target Name |
Carbonic anhydrase XIV (CA-XIV)
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| Synonyms |
UNQ690/PRO1335; Carbonic anhydrase 14; Carbonate dehydratase XIV
Click to Show/Hide
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| Gene Name |
CA14
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Bacterial infection [ICD-11: 1A00-1C4Z] | |||||
| 2 | Inborn metabolism deficiency [ICD-11: 5C50-5C59] | |||||
| Function |
Reversible hydration of carbon dioxide.
Click to Show/Hide
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| BioChemical Class |
Alpha-carbonic anhydrase
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| UniProt ID | ||||||
| EC Number |
EC 4.2.1.1
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| Sequence |
MLFSALLLEVIWILAADGGQHWTYEGPHGQDHWPASYPECGNNAQSPIDIQTDSVTFDPD
LPALQPHGYDQPGTEPLDLHNNGHTVQLSLPSTLYLGGLPRKYVAAQLHLHWGQKGSPGG SEHQINSEATFAELHIVHYDSDSYDSLSEAAERPQGLAVLGILIEVGETKNIAYEHILSH LHEVRHKDQKTSVPPFNLRELLPKQLGQYFRYNGSLTTPPCYQSVLWTVFYRRSQISMEQ LEKLQGTLFSTEEEPSKLLVQNYRALQPLNQRMVFASFIQAGSSYTTGEMLSLGVGILVG CLCLLLAVYFIARKIRKKRLENRKSVVFTSAQATTEA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Sulfamylon | Drug Info | Approved | Bacterial infection | [2], [3] | |
| 2 | TRIENTINE | Drug Info | Approved | Inborn error of metabolism | [2] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Curcumin | Drug Info | Phase 3 | Solid tumour/cancer | [4], [5] | |
| 2 | Coumate | Drug Info | Phase 2 | Breast cancer | [6] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 74 Inhibitor drugs | + | ||||
| 1 | Sulfamylon | Drug Info | [1] | |||
| 2 | TRIENTINE | Drug Info | [7] | |||
| 3 | Curcumin | Drug Info | [8] | |||
| 4 | PARABEN | Drug Info | [9] | |||
| 5 | PHENOL | Drug Info | [8] | |||
| 6 | Coumate | Drug Info | [10] | |||
| 7 | FERULIC ACID | Drug Info | [9] | |||
| 8 | SPERMINE | Drug Info | [7] | |||
| 9 | 2,3-dihydro-1H-indene-5-sulfonamide | Drug Info | [11] | |||
| 10 | 2,4-Disulfamyltrifluoromethylaniline | Drug Info | [1] | |||
| 11 | 2-acetamido-2,3-dihydro-1H-indene-5-sulfonic acid | Drug Info | [11] | |||
| 12 | 2-amino-2,3-dihydro-1H-indene-5-sulfonamide | Drug Info | [11] | |||
| 13 | 2-Amino-benzenesulfonamide | Drug Info | [1] | |||
| 14 | 2-Amino-indan-5-sulfonic acid | Drug Info | [11] | |||
| 15 | 2-oxo-2H-chromene-3-carboxylic acid | Drug Info | [12] | |||
| 16 | 2-oxo-2H-thiochromene-3-carboxylic acid | Drug Info | [12] | |||
| 17 | 3-Amino-benzenesulfonamide | Drug Info | [1] | |||
| 18 | 4,4'-thiodipyridine-3-sulfonamide | Drug Info | [13] | |||
| 19 | 4-(2-AMINOETHYL)BENZENESULFONAMIDE | Drug Info | [1] | |||
| 20 | 4-(2-Hydroxy-ethyl)-benzenesulfonamide | Drug Info | [1] | |||
| 21 | 4-(2-Methyl-8-quinolinoxy)-3-pyridinesulfonamide | Drug Info | [13] | |||
| 22 | 4-(2-Propynylthio)pyridine-3-sulfonamide | Drug Info | [13] | |||
| 23 | 4-(5-Methyl-2-pirazolino)-3-pyridinesulfonamide | Drug Info | [13] | |||
| 24 | 4-(Allylamino)-3-pyridinesulfonamide | Drug Info | [13] | |||
| 25 | 4-(Carbamolymethylthio)pyridine-3-sulfonamide | Drug Info | [13] | |||
| 26 | 4-(Cyanomethylthio)pyridine-3-sulfonamide | Drug Info | [13] | |||
| 27 | 4-(hydroxymethyl)benzenesulfonamide | Drug Info | [1] | |||
| 28 | 4-(Methylhydrazino)-3-pyridinesulfonamide | Drug Info | [13] | |||
| 29 | 4-(Quinolinoxy)-3-pyridinesulfonamide | Drug Info | [13] | |||
| 30 | 4-Amino-3-bromo-benzenesulfonamide | Drug Info | [1] | |||
| 31 | 4-Amino-3-chloro-benzenesulfonamide | Drug Info | [1] | |||
| 32 | 4-Amino-3-fluoro-benzenesulfonamide | Drug Info | [1] | |||
| 33 | 4-Amino-3-iodo-benzenesulfonamide | Drug Info | [1] | |||
| 34 | 4-AMINOPHENOL | Drug Info | [14] | |||
| 35 | 4-Benzythiopyridine-3-sulfonamide | Drug Info | [13] | |||
| 36 | 4-Ethoxy-3-pyridinesulfonamide | Drug Info | [13] | |||
| 37 | 4-Hydrazino-3-pyridinesulfonamide | Drug Info | [13] | |||
| 38 | 4-Hydrazino-benzenesulfonamide | Drug Info | [1] | |||
| 39 | 4-Methylthiopyridine-3-sulfonamide | Drug Info | [13] | |||
| 40 | 6-(aminomethyl)-2H-chromen-2-one | Drug Info | [12] | |||
| 41 | 6-(hydroxymethyl)-2H-chromen-2-one | Drug Info | [12] | |||
| 42 | 6-Hydroxy-benzothiazole-2-sulfonic acid amide | Drug Info | [1] | |||
| 43 | 6-methoxy-2-oxo-2H-chromene-3-carboxylic acid | Drug Info | [12] | |||
| 44 | 6-methyl-2-oxo-2H-chromene-3-carboxylic acid | Drug Info | [12] | |||
| 45 | 7-(benzyloxy)-2H-chromen-2-one | Drug Info | [12] | |||
| 46 | 7-butoxy-2H-chromen-2-one | Drug Info | [12] | |||
| 47 | 7-methoxy-2-oxo-2H-chromene-4-carboxylic acid | Drug Info | [12] | |||
| 48 | 7-phenethoxy-2H-chromen-2-one | Drug Info | [12] | |||
| 49 | 7-propoxy-2H-chromen-2-one | Drug Info | [12] | |||
| 50 | 8-methoxy-2-oxo-2H-chromene-3-carboxylic acid | Drug Info | [12] | |||
| 51 | BENZOLAMIDE | Drug Info | [1] | |||
| 52 | Beta-D-Mannose | Drug Info | [15] | |||
| 53 | Carzenide | Drug Info | [1] | |||
| 54 | CATECHIN | Drug Info | [8] | |||
| 55 | CL-5343 | Drug Info | [16] | |||
| 56 | COUMARIN | Drug Info | [12] | |||
| 57 | Decane-1,10-diyl disulfamate | Drug Info | [17] | |||
| 58 | Decyl sulfamate | Drug Info | [17] | |||
| 59 | ELLAGIC ACID | Drug Info | [9] | |||
| 60 | ETHOXYCOUMARIN | Drug Info | [12] | |||
| 61 | Ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate | Drug Info | [12] | |||
| 62 | GALLICACID | Drug Info | [9] | |||
| 63 | HERNIARIN | Drug Info | [12] | |||
| 64 | Hexane-1,6-diamine | Drug Info | [7] | |||
| 65 | N-propynyl amidebenzenesulphonide | Drug Info | [18] | |||
| 66 | N1-(2-aminoethyl)ethane-1,2-diamine | Drug Info | [7] | |||
| 67 | N1-(naphthalen-1-yl)ethane-1,2-diamine | Drug Info | [7] | |||
| 68 | Octane-1,8-diyl disulfamate | Drug Info | [17] | |||
| 69 | Octyl sulfamate | Drug Info | [17] | |||
| 70 | P-Coumaric Acid | Drug Info | [9] | |||
| 71 | Pentane-1,5-diamine | Drug Info | [7] | |||
| 72 | Prop-2-ynyl 4-sulfamoylbenzoate | Drug Info | [18] | |||
| 73 | RESORCINOL | Drug Info | [14] | |||
| 74 | Syringic Acid | Drug Info | [9] | |||
| 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: Acetazolamide | Ligand Info | |||||
| Structure Description | The crystal structure of the human carbonic anhydrase XIV | PDB:4LU3 | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [19] |
| PDB Sequence |
HWTYEGPHGQ
13 DHWPASYPEC23 GNNAQSPIDI33 QTDSVTFDPD43 LPALQPHGYD52 QPGTEPLDLH 60 NNGHTVQLSL70 PSTLYLGGLP85 RKYVAAQLHL95 HWGQKGSPGG104 SEHQINSEAT 114 FAELHIVHYD124 SDSYDSLSEA134 AERPQGLAVL144 GILIEVGETK153 NIAYEHILSH 163 LHEVRHKDQK173 TSVPPFNLRE183 LLPKQLGQYF192 RYNGSLTTPP202 CYQSVLWTVF 212 YRRSQISMEQ222 LEKLQGTLFS231 TEEEPSKLLV242 QNYRALQPLN252 QRMVFASFIQ 262 AGSSYT
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| Ligand Name: 4'-(4-Aminobenzoyl)biphenyl-4-Sulfonamide | Ligand Info | |||||
| Structure Description | The crystal structure of the human carbonic anhydrase XIV in complex with a 1,1'-biphenyl-4-sulfonamide inhibitor. | PDB:5CJF | ||||
| Method | X-ray diffraction | Resolution | 1.83 Å | Mutation | No | [20] |
| PDB Sequence |
HWTYEGPHGQ
13 DHWPASYPEC23 GNNAQSPIDI33 QTDSVTFDPD43 LPALQPHGYD52 QPGTEPLDLH 60 NNGHTVQLSL70 PSTLYLGGLP85 RKYVAAQLHL95 HWGQKGSPGG104 SEHQINSEAT 114 FAELHIVHYD124 SDSYDSLSEA134 AERPQGLAVL144 GILIEVGETK153 NIAYEHILSH 163 LHEVRHKDQK173 TSVPPFNLRE183 LLPKQLGQYF192 RYNGSLTTPP202 CYQSVLWTVF 212 YRRSQISMEQ222 LEKLQGTLFS231 TEEEPSKLLV242 QNYRALQPLN252 QRMVFASFIQ 262 AGSSYTT
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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).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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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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| Nitrogen metabolism | hsa00910 | Affiliated Target |
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| Class: Metabolism => Energy metabolism | Pathway Hierarchy | ||
| 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) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Nitrogen metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Reversible hydration of carbon dioxide | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Reversible Hydration of Carbon Dioxide | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Carbonic anhydrase inhibitors: inhibition of the transmembrane isozyme XIV with sulfonamides. Bioorg Med Chem Lett. 2005 Sep 1;15(17):3828-33. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | ClinicalTrials.gov (NCT00634166) Prospective Evaluation of the Effects of Topical Therapy With Sulfamylon For 5% Topical Solution on Autograft Healing in Subjects With Thermal Injuries Requiring Meshed Autografts: A Comparison to a Historical Control Group. U.S. National Institutes of Health. | |||||
| REF 4 | 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: 7000). | |||||
| REF 5 | Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68. | |||||
| REF 6 | Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer. Expert Rev Anticancer Ther. 2011 Feb;11(2):179-83. | |||||
| REF 7 | Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule. J Med Chem. 2010 Aug 12;53(15):5511-22. | |||||
| REF 8 | Carbonic anhydrase inhibitors. Antioxidant polyphenols effectively inhibit mammalian isoforms I-XV. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5050-3. | |||||
| REF 9 | Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids. Bioorg Med Chem. 2010 Mar 15;18(6):2159-2164. | |||||
| REF 10 | Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-r... Bioorg Med Chem Lett. 2008 Aug 1;18(15):4282-6. | |||||
| REF 11 | Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: structure-activity relationship and pharmacological evaluation. Eur J Med Chem. 2008 Dec;43(12):2853-60. | |||||
| REF 12 | Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J Med Chem. 2010 Jan 14;53(1):335-44. | |||||
| REF 13 | Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associa... Eur J Med Chem. 2010 Jun;45(6):2396-404. | |||||
| REF 14 | Carbonic anhydrase inhibitors: inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid. Bioorg Med Chem. 2008 Aug 1;16(15):7424-8. | |||||
| REF 15 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 16 | Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a l... Bioorg Med Chem Lett. 2010 Aug 1;20(15):4376-81. | |||||
| REF 17 | Carbonic anhydrase inhibitors. Comparison of aliphatic sulfamate/bis-sulfamate adducts with isozymes II and IX as a platform for designing tight-bi... J Med Chem. 2009 Oct 8;52(19):5990-8. | |||||
| REF 18 | Inhibition of membrane-associated carbonic anhydrase isozymes IX, XII and XIV with a library of glycoconjugate benzenesulfonamides. Bioorg Med Chem Lett. 2007 Feb 15;17(4):987-92. | |||||
| REF 19 | The structural comparison between membrane-associated human carbonic anhydrases provides insights into drug design of selective inhibitors. Biopolymers. 2014 Jul;101(7):769-78. | |||||
| REF 20 | Discovery of 1,1'-Biphenyl-4-sulfonamides as a New Class of Potent and Selective Carbonic Anhydrase XIV Inhibitors. J Med Chem. 2015 Nov 12;58(21):8564-72. | |||||
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