Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN44YQ5)

• DOT Name: Transmembrane protease serine 2 (TMPRSS2)
• Synonyms: EC 3.4.21.122; Serine protease 10
• Gene Name: TMPRSS2
• UniProt ID: TMPS2_HUMAN
• PDB ID: 7MEQ
• EC Number: 3.4.21.122
• Pfam ID: PF15494 ; PF00089
• Sequence:
  MALNSGSPPAIGPYYENHGYQPENPYPAQPTVVPTVYEVHPAQYYPSPVPQYAPRVLTQA
  SNPVVCTQPKSPSGTVCTSKTKKALCITLTLGTFLVGAALAAGLLWKFMGSKCSNSGIEC
  DSSGTCINPSNWCDGVSHCPGGEDENRCVRLYGPNFILQVYSSQRKSWHPVCQDDWNENY
  GRAACRDMGYKNNFYSSQGIVDDSGSTSFMKLNTSAGNVDIYKKLYHSDACSSKAVVSLR
  CIACGVNLNSSRQSRIVGGESALPGAWPWQVSLHVQNVHVCGGSIITPEWIVTAAHCVEK
  PLNNPWHWTAFAGILRQSFMFYGAGYQVEKVISHPNYDSKTKNNDIALMKLQKPLTFNDL
  VKPVCLPNPGMMLQPEQLCWISGWGATEEKGKTSEVLNAAKVLLIETQRCNSRYVYDNLI
  TPAMICAGFLQGNVDSCQGDSGGPLVTSKNNIWWLIGDTSWGSGCAKAYRPGVYGNVMVF
  TDWIYRQMRADG
• Function: Plasma membrane-anchored serine protease that cleaves at arginine residues. Participates in proteolytic cascades of relevance for the normal physiologic function of the prostate. Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells. In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia; (Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry. The cleavage of SARS-COV2 spike glycoprotein occurs between the S2 and S2' site. Upon SARS-CoV-2 infection, increases syncytia formation by accelerating the fusion process. Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.
• Tissue Specificity: Expressed in several tissues that comprise large populations of epithelial cells with the highest level of transcripts measured in the prostate gland. Expressed in type II pneumocytes in the lung (at protein level). Expressed strongly in small intestine. Also expressed in colon, stomach and salivary gland. Coexpressed with ACE2 within lung type II pneumocytes, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells (Ref.21).
• KEGG Pathway:
  Influenza A (hsa05164)
  Coro.virus disease - COVID-19 (hsa05171)
  Transcriptio.l misregulation in cancer (hsa05202)
  Prostate cancer (hsa05215)
• Reactome Pathway:
  Attachment and Entry (R-HSA-9694614)
  Induction of Cell-Cell Fusion (R-HSA-9733458)
  Attachment and Entry (R-HSA-9678110)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Transmembrane protease serine 2 (TMPRSS2) affects the response to substance of Afimoxifene.	[29]
NAPQI	DM8F5LR	Investigative	Transmembrane protease serine 2 (TMPRSS2) affects the response to substance of NAPQI.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protease serine 2 (TMPRSS2).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[13]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[14]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Isoniazid	DM5JVS3	Approved	Isoniazid affects the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Ciprofloxacin XR	DM2NLS9	Approved	Ciprofloxacin XR decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Omeprazole	DM471KJ	Approved	Omeprazole increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Flutamide	DMK0O7U	Approved	Flutamide increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Imipramine	DM2NUH3	Approved	Imipramine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Allopurinol	DMLPAOB	Approved	Allopurinol decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Naproxen	DMZ5RGV	Approved	Naproxen increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Quinidine	DMLPICK	Approved	Quinidine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Diazepam	DM08E9O	Approved	Diazepam increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Benzbromarone	DMC3YUA	Approved	Benzbromarone increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Chloramphenicol	DMFXEWT	Approved	Chloramphenicol increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Perhexiline	DMINO7Z	Approved	Perhexiline increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Propylthiouracil	DM6D7N8	Approved	Propylthiouracil increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Glibenclamide	DM8JXPZ	Approved	Glibenclamide increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Promethazine	DM6I5GR	Approved	Promethazine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Ethambutol	DMR87LC	Approved	Ethambutol increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Famotidine	DMRL3AB	Approved	Famotidine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Riluzole	DMECBWN	Approved	Riluzole decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[15]
Doxepin	DMPI98T	Approved	Doxepin increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Danazol	DML8KTN	Approved	Danazol increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Tolbutamide	DM02AWV	Approved	Tolbutamide increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Disopyramide	DM5SYZP	Approved	Disopyramide increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Hydroxyzine	DMF8Y74	Approved	Hydroxyzine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Chlorpheniramine	DM5URA2	Approved	Chlorpheniramine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Nitrofurantoin	DM7PQIK	Approved	Nitrofurantoin increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Papaverine	DMCA9QP	Approved	Papaverine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Buspirone	DMBS632	Approved	Buspirone increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Ajmaline	DMDJW5K	Approved	Ajmaline increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Moxisylyte	DMFCLYW	Approved	Moxisylyte increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[18]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[19]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[20]
Camostat mesylate	DMVLXMG	Phase 2/3 Trial	Camostat mesylate decreases the activity of Transmembrane protease serine 2 (TMPRSS2).	[21]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[22]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[15]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[24]
Nimesulide	DMR1NMD	Terminated	Nimesulide increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transmembrane protease serine 2 (TMPRSS2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[26]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[27]
EPZ-004777	DMLN4V5	Investigative	EPZ-004777 decreases the expression of Transmembrane protease serine 2 (TMPRSS2).	[28]
Fluphenazine	DMIT8LX	Investigative	Fluphenazine increases the expression of Transmembrane protease serine 2 (TMPRSS2).	[10]

1 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 increases the methylation of Transmembrane protease serine 2 (TMPRSS2).	[23]

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