Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTRZGU7)

• DOT Name: Angiotensin-converting enzyme 2 (ACE2)
• Synonyms: EC 3.4.17.23; Angiotensin-converting enzyme homolog; ACEH; Angiotensin-converting enzyme-related carboxypeptidase; ACE-related carboxypeptidase; EC 3.4.17.-; Metalloprotease MPROT15
• Gene Name: ACE2
• UniProt ID: ACE2_HUMAN
• PDB ID: 1R42 ; 1R4L ; 2AJF ; 3D0G ; 3D0H ; 3D0I ; 3KBH ; 3SCI ; 3SCJ ; 3SCK ; 3SCL ; 6ACG ; 6ACJ ; 6ACK ; 6CS2 ; 6LZG ; 6M0J ; 6M17 ; 6M18 ; 6M1D ; 6VW1 ; 7A91 ; 7A92 ; 7A94 ; 7A95 ; 7A96 ; 7A97 ; 7A98 ; 7BH9 ; 7CT5 ; 7DDO ; 7DDP ; 7DF4 ; 7DMU ; 7DQA ; 7DRV ; 7DWX ; 7DX4 ; 7DX5 ; 7DX6 ; 7DX7 ; 7DX8 ; 7DX9 ; 7E7E ; 7EDJ ; 7EFP ; 7EFR ; 7EKC ; 7EKE ; 7EKF ; 7EKG ; 7EKH ; 7FDG ; 7FDH ; 7FDI ; 7FEM ; 7JVO ; 7KJ2 ; 7KJ3 ; 7KJ4 ; 7KMB ; 7KMS ; 7KMZ ; 7KNB ; 7KNE ; 7KNH ; 7KNI ; 7L0N ; 7L7F ; 7LO4 ; 7MJM ; 7MJN ; 7NXC ; 7P19 ; 7P55 ; 7P8I ; 7P8J ; 7PKI ; 7R0Z ; 7R10 ; 7R11 ; 7R12 ; 7R1A ; 7RPV ; 7SN0 ; 7SXX ; 7SXY ; 7SXZ ; 7SY0 ; 7SY1 ; 7SY2 ; 7SY3 ; 7SY4 ; 7SY5 ; 7SY6 ; 7SY7 ; 7SY8 ; 7T9K ; 7T9L ; 7TEW ; 7TEX ; 7TEZ ; 7TF0 ; 7TN0 ; 7U0N ; 7UFK ; 7UFL ; 7V61 ; 7V7Z ; 7V80 ; 7V81 ; 7V82 ; 7V83 ; 7V84 ; 7V85 ; 7V86 ; 7V87 ; 7V88 ; 7V89 ; 7V8A ; 7V8B ; 7VIB ; 7VX4 ; 7VX5 ; 7VX9 ; 7VXA ; 7VXB ; 7VXC ; 7VXD ; 7VXF ; 7VXK ; 7VXM ; 7W98 ; 7W99 ; 7W9B ; 7W9C ; 7W9I ; 7WBL ; 7WBP ; 7WBQ ; 7WGB ; 7WGC ; 7WHH ; 7WK4 ; 7WK5 ; 7WK6 ; 7WNM ; 7WPA ; 7WPB ; 7WPC ; 7WS8 ; 7WS9 ; 7WSA ; 7WVP ; 7WVQ ; 7XAZ ; 7XB0 ; 7XB1 ; 7XBF ; 7XBG ; 7XBH ; 7XCH ; 7XCI ; 7XCP ; 7XID ; 7XO7 ; 7XO8 ; 7XO9 ; 7XWA ; 7Y1Y ; 7Y1Z ; 7Y20 ; 7Y21 ; 7Y75 ; 7Y76 ; 7Y9Z ; 7YA0 ; 7YA1 ; 7YDI ; 7YEG ; 7YHW ; 7YJ3 ; 7YR2 ; 7YR3 ; 7YR4 ; 7ZDQ ; 7ZF7 ; 8AQS ; 8ASY ; 8B9P ; 8BFW ; 8BN1 ; 8BYJ ; 8DF5 ; 8DLJ ; 8DLK ; 8DLM ; 8DLN ; 8DLP ; 8DLQ ; 8DLU ; 8DLV ; 8DM5 ; 8DM6 ; 8DV1 ; 8DV2 ; 8E7M ; 8FXB ; 8FXC ; 8H06 ; 8H5C ; 8I91 ; 8I92 ; 8I93 ; 8IF2 ; 8IOU ; 8IOV ; 8S9G ; 8SPH ; 8SPI ; 8WRH ; 8WRL ; 8WRM ; 8WRO
• EC Number: 3.4.17.-; 3.4.17.23
• Pfam ID: PF16959 ; PF01401
• Sequence:
  MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQ
  NMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTIL
  NTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLY
  EEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHL
  HAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQ
  AWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILM
  CTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKS
  IGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEM
  KREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLH
  KCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNK
  NSFVGWSTDWSPYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKN
  QMILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLNDN
  SLEFLGIQPTLGPPNQPPVSIWLIVFGVVMGVIVVGIVILIFTGIRDRKKKNKARSGENP
  YASIDISKGENNPGFQNTDDVQTSF
• Function: Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II. Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin. Also cleaves other biological peptides, such as apelins (apelin-13, [Pyr1]apelin-13, apelin-17, apelin-36), casomorphins (beta-casomorphin-7, neocasomorphin) and dynorphin A with high efficiency. In addition, ACE2 C-terminus is homologous to collectrin and is responsible for the trafficking of the neutral amino acid transporter SL6A19 to the plasma membrane of gut epithelial cells via direct interaction, regulating its expression on the cell surface and its catalytic activity ; (Microbial infection) Acts as a receptor for human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63; [Isoform 2]: Non-functional as a carboxypeptidase; [Isoform 2]: (Microbial infection) Non-functional as a receptor for human coronavirus SARS-CoV-2.
• Tissue Specificity: Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells (at protein level) . Expressed in enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level) . Expressed in the renal proximal tubule and the small intestine (at protein level) . Expressed in heart, kidney, testis, and gastrointestinal system (at protein level) . In lung, expressed at low levels in some alveolar type 2 cells, the expression seems to be individual-specific (at protein level) . Expressed in nasal epithelial cells (at protein level) . Coexpressed with TMPRSS2 within some lung alveolar type 2 cells, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells . Coexpressed with TMPRSS4 within mature enterocytes .; [Isoform 2]: Expressed in nasal and bronchial epithelial cells (at protein level).
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Protein digestion and absorption (hsa04974)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Attachment and Entry (R-HSA-9678110)
  Potential therapeutics for SARS (R-HSA-9679191)
  Attachment and Entry (R-HSA-9694614)
  Induction of Cell-Cell Fusion (R-HSA-9733458)
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)
• BioCyc Pathway: MetaCyc:ENSG00000130234-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Benazepril	DMH1M9B	Approved	Angiotensin-converting enzyme 2 (ACE2) increases the response to substance of Benazepril.	[14]
Captopril	DM458UM	Approved	Angiotensin-converting enzyme 2 (ACE2) decreases the response to substance of Captopril.	[15]
Irbesartan	DMTP1DC	Investigative	Angiotensin-converting enzyme 2 (ACE2) affects the response to substance of Irbesartan.	[16]

58 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Angiotensin-converting enzyme 2 (ACE2).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Isoniazid	DM5JVS3	Approved	Isoniazid decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Penicillamine	DM40EF6	Approved	Penicillamine increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Tetracycline	DMZA017	Approved	Tetracycline increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Methimazole	DM25FL8	Approved	Methimazole decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Omeprazole	DM471KJ	Approved	Omeprazole decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Flutamide	DMK0O7U	Approved	Flutamide decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Imipramine	DM2NUH3	Approved	Imipramine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Quinidine	DMLPICK	Approved	Quinidine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Diazepam	DM08E9O	Approved	Diazepam decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Chloramphenicol	DMFXEWT	Approved	Chloramphenicol decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Propylthiouracil	DM6D7N8	Approved	Propylthiouracil decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Glibenclamide	DM8JXPZ	Approved	Glibenclamide decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Ethambutol	DMR87LC	Approved	Ethambutol increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Doxepin	DMPI98T	Approved	Doxepin decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Danazol	DML8KTN	Approved	Danazol decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Disopyramide	DM5SYZP	Approved	Disopyramide increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Labetalol	DMK8U72	Approved	Labetalol increases the activity of Angiotensin-converting enzyme 2 (ACE2).	[8]
Hydroxyzine	DMF8Y74	Approved	Hydroxyzine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Lomustine	DMMWSUL	Approved	Lomustine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Griseofulvin	DMK54YG	Approved	Griseofulvin decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Papaverine	DMCA9QP	Approved	Papaverine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Dantrolene	DM1D8XY	Approved	Dantrolene increases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Aprindine	DMBXWU8	Approved	Aprindine increases the activity of Angiotensin-converting enzyme 2 (ACE2).	[8]
Chlorpropamide	DMPHZQE	Approved	Chlorpropamide decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Moxisylyte	DMFCLYW	Approved	Moxisylyte decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
ORE-1001	DM471ZH	Phase 1/2	ORE-1001 decreases the activity of Angiotensin-converting enzyme 2 (ACE2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[11]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
PMID28454500-Compound-96	DM2A75P	Patented	PMID28454500-Compound-96 decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[13]
Nimesulide	DMR1NMD	Terminated	Nimesulide decreases the expression of Angiotensin-converting enzyme 2 (ACE2).	[2]
Diminazene	DM2Y0AI	Investigative	Diminazene increases the activity of Angiotensin-converting enzyme 2 (ACE2).	[8]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Loratadine	DMF3AN7	Approved	Loratadine affects the binding of Angiotensin-converting enzyme 2 (ACE2).	[7]
Desloratadine	DM56YN7	Approved	Desloratadine affects the binding of Angiotensin-converting enzyme 2 (ACE2).	[7]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Angiotensin-converting enzyme 2 (ACE2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Angiotensin-converting enzyme 2 (ACE2).	[12]

References

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• [2] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
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• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [6] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [7] Testing of the inhibitory effects of loratadine and desloratadine on SARS-CoV-2 spike pseudotyped virus viropexis. Chem Biol Interact. 2021 Apr 1;338:109420. doi: 10.1016/j.cbi.2021.109420. Epub 2021 Feb 18.
• [8] Prediction of off-target effects on angiotensin-converting enzyme 2. J Biomol Screen. 2011 Sep;16(8):878-85. doi: 10.1177/1087057111413919. Epub 2011 Aug 22.
• [9] Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells. Eur J Pharmacol. 2016 Mar 5;774:25-33. doi: 10.1016/j.ejphar.2016.01.007. Epub 2016 Feb 3.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation. Am J Physiol Lung Cell Mol Physiol. 2016 Nov 1;311(5):L846-L854. doi: 10.1152/ajplung.00449.2015. Epub 2016 Sep 16.
• [14] Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J Hum Hypertens. 2016 Dec;30(12):766-771. doi: 10.1038/jhh.2016.24. Epub 2016 Apr 28.
• [15] Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women. Clin Pharmacol Ther. 2007 Aug;82(2):187-96. doi: 10.1038/sj.clpt.6100214. Epub 2007 May 2.
• [16] Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J Hypertens. 2001 Oct;19(10):1783-7. doi: 10.1097/00004872-200110000-00012.