Target Information
| Target General Information | Top | |||||
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| Target ID |
T98311
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| Target Name |
HUMAN angiotensin-converting enzyme (ACE)
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| Synonyms |
Kininase II; Dipeptidyl carboxypeptidase I; DCP1; DCP; CD143 antigen; CD143; ACE
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| Gene Name |
SLC33A1
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| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Heart failure [ICD-11: BD10-BD1Z] | |||||
| 2 | Hypertension [ICD-11: BA00-BA04] | |||||
| Function |
Able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin.
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| BioChemical Class |
Glycosylase
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| UniProt ID | ||||||
| EC Number |
EC 3.2.1.-
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| Sequence |
MGAASGRRGPGLLLPLPLLLLLPPQPALALDPGLQPGNFSADEAGAQLFAQSYNSSAEQV
LFQSVAASWAHDTNITAENARRQEEAALLSQEFAEAWGQKAKELYEPIWQNFTDPQLRRI IGAVRTLGSANLPLAKRQQYNALLSNMSRIYSTAKVCLPNKTATCWSLDPDLTNILASSR SYAMLLFAWEGWHNAAGIPLKPLYEDFTALSNEAYKQDGFTDTGAYWRSWYNSPTFEDDL EHLYQQLEPLYLNLHAFVRRALHRRYGDRYINLRGPIPAHLLGDMWAQSWENIYDMVVPF PDKPNLDVTSTMLQQGWNATHMFRVAEEFFTSLELSPMPPEFWEGSMLEKPADGREVVCH ASAWDFYNRKDFRIKQCTRVTMDQLSTVHHEMGHIQYYLQYKDLPVSLRRGANPGFHEAI GDVLALSVSTPEHLHKIGLLDRVTNDTESDINYLLKMALEKIAFLPFGYLVDQWRWGVFS GRTPPSRYNFDWWYLRTKYQGICPPVTRNETHFDAGAKFHVPNVTPYIRYFVSFVLQFQF HEALCKEAGYEGPLHQCDIYRSTKAGAKLRKVLQAGSSRPWQEVLKDMVGLDALDAQPLL KYFQPVTQWLQEQNQQNGEVLGWPEYQWHPPLPDNYPEGIDLVTDEAEASKFVEEYDRTS QVVWNEYAEANWNYNTNITTETSKILLQKNMQIANHTLKYGTQARKFDVNQLQNTTIKRI IKKVQDLERAALPAQELEEYNKILLDMETTYSVATVCHPNGSCLQLEPDLTNVMATSRKY EDLLWAWEGWRDKAGRAILQFYPKYVELINQAARLNGYVDAGDSWRSMYETPSLEQDLER LFQELQPLYLNLHAYVRRALHRHYGAQHINLEGPIPAHLLGNMWAQTWSNIYDLVVPFPS APSMDTTEAMLKQGWTPRRMFKEADDFFTSLGLLPVPPEFWNKSMLEKPTDGREVVCHAS AWDFYNGKDFRIKQCTTVNLEDLVVAHHEMGHIQYFMQYKDLPVALREGANPGFHEAIGD VLALSVSTPKHLHSLNLLSSEGGSDEHDINFLMKMALDKIAFIPFSYLVDQWRWRVFDGS ITKENYNQEWWSLRLKYQGLCPPVPRTQGDFDPGAKFHIPSSVPYIRYFVSFIIQFQFHE ALCQAAGHTGPLHKCDIYQSKEAGQRLATAMKLGFSRPWPEAMQLITGQPNMSASAMLSY FKPLLDWLRTENELHGEKLGWPQYNWTPNSARSEGPLPDSGRVSFLGLDLDAQQARVGQW LLLFLGIALLVATLGLSQRLFSIRHRSLHRHSHGPQFGSEVELRHS 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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| Drugs in Phase 3 Trial | [+] 1 | + | ||||
| 1 | Captopril | Drug Info | Approved | Hypertension | [2] | |
| Investigative Agents | [+] 1 | + | ||||
| 1 | Lisinopril | Drug Info | Approved | Hypertension | [3] | |
| Drugs in Phase 2 Trial | [+] 1 | + | ||||
| 1 | Ramipril | Drug Info | Approved | Acute heart failure | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | Captopril | Drug Info | [5] | |||
| 2 | Ramipril | Drug Info | [5] | |||
| 3 | Lisinopril | 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: L-glutamine | Ligand Info | |||||
| Structure Description | Crystal structure of the Angiotensin-1 converting enzyme N-domain in complex with amyloid-beta 10-16 | PDB:5AM9 | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | Yes | [6] |
| PDB Sequence |
LDPGLQPGQF
10 SADEAGAQLF20 AQSYQSSAEQ30 VLFQSVAASW40 AHDTNITAEN50 ARRQEEAALL 60 SQEFAEAWGQ70 KAKELYEPIW80 QQFTDPQLRR90 IIGAVRTLGS100 ANLPLAKRQQ 110 YNALLSQMSR120 IYSTAKVCLT135 CWSLDPDLTN145 ILASSRSYAM155 LLFAWEGWHN 165 AAGIPLKPLY175 EDFTALSNEA185 YKQDGFTDTG195 AYWRSWYNSP205 TFEDDLEHLY 215 QQLEPLYLNL225 HAFVRRALHR235 RYGDRYINLR245 GPIPAHLLGD255 MWAQSWENIY 265 DMVVPFPDKP275 NLDVTSTMLQ285 QGWQATHMFR295 VAEEFFTSLE305 LSPMPPEFWE 315 GSMLEKPADG325 REVVCHASAW335 DFYNRKDFRI345 KQCTRVTMDQ355 LSTVHHEMGH 365 IQYYLQYKDL375 PVSLRRGANP385 GFHEAIGDVL395 ALSVSTPEHL405 HKIGLLDRVT 415 NDTESDINYL425 LKMALEKIAF435 LPFGYLVDQW445 RWGVFSGRTP455 PSRYNFDWWY 465 LRTKYQGICP475 PVTRNETHFD485 AGAKFHVPNV495 TPYIRYFVSF505 VLQFQFHEAL 515 CKEAGYEGPL525 HQCDIYRSTK535 AGAKLRKVLR545 AGSSRPWQEV555 LKDMVGLDAL 565 DAQPLLKYFQ575 LVTQWLQEQN585 QQNGEVLGWP595 EYQWHPPLPD605 NYP |
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| Ligand Name: Boric acid | Ligand Info | |||||
| Structure Description | Crystal structure of human Angiotensin-1 converting enzyme C-domain in complex with Omapatrilat. | PDB:6H5W | ||||
| Method | X-ray diffraction | Resolution | 1.37 Å | Mutation | Yes | [7] |
| PDB Sequence |
DEAEASKFVE
49 EYDRTSQVVW59 NEYAGANWNY69 NTNITTETSK79 ILLQKNMQIA89 QHTLKYGTQA 99 RKFDVNQLQN109 TTIKRIIKKV119 QDLERAALPA129 QELEEYNKIL139 LDMETTYSVA 149 TVCHPQGSCL159 QLEPDLTNVM169 ATSRKYEDLL179 WAWEGWRDKA189 GRAILQFYPK 199 YVELINQAAR209 LNGYVDAGDS219 WRSMYETPSL229 EQDLERLFQE239 LQPLYLNLHA 249 YVRRALHRHY259 GAQHINLEGP269 IPAHLLGNMW279 AQTWSNIYDL289 VVPFPSAPSM 299 DTTEAMLKQG309 WTPRRMFKEA319 DDFFTSLGLL329 PVPPEFWQKS339 MLEKPTDGRE 349 VVCHASAWDF359 YNGKDFRIKQ369 CTTVNLEDLV379 VAHHEMGHIQ389 YFMQYKDLPV 399 ALREGANPGF409 HEAIGDVLAL419 SVSTPKHLHS429 LNLLSSEGGS439 DEHDINFLMK 449 MALDKIAFIP459 FSYLVDQWRW469 RVFDGSITKE479 NYNQEWWSLR489 LKYQGLPPVP 500 RTQGDFDPGA510 KFHIPSSVPY520 IRYFVSFIIQ530 FQFHEALCQA540 AGHTGPLHKC 550 DIYQSKEAGQ560 RLATAMKLGF570 SRPWPEAMQL580 ITGQPQMSAS590 AMLSYFKPLL 600 DWLRTENELH610 GEKLGWPQYN620 WTPNS
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THR282
4.092
TYR287
2.743
PHE293
3.842
SER298
3.110
VAL379
3.289
VAL380
4.027
HIS383
3.273
ASP415
2.713
PRO424
2.729
LEU427
4.643
LEU433
3.028
GLU436
2.666
ASP440
3.045
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| 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 |
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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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| Renin-angiotensin system | hsa04614 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Renin secretion | hsa04924 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 1.59E-04 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 1.67E-01 |
| Neighborhood connectivity | 4.15E+01 | Topological coefficient | 2.65E-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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc. 2020 Apr 7;9(7):e016219. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074532. | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 202392. | |||||
| REF 5 | Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep. 2020 Apr 14;22(5):31. | |||||
| REF 6 | Kinetic and structural characterization of amyloid-beta peptide hydrolysis by human angiotensin-1-converting enzyme. FEBS J. 2016 Mar;283(6):1060-76. | |||||
| REF 7 | Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design. J Med Chem. 2018 Nov 21;61(22):10141-10154. | |||||
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