Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNFSM49)

• DOT Name: Prothrombin (F2)
• Synonyms: EC 3.4.21.5; Coagulation factor II
• Gene Name: F2
• Related Disease:
  Congenital prothrombin deficiency
  Venous thrombosis
• UniProt ID: THRB_HUMAN
• PDB ID: 1A2C ; 1A3B ; 1A3E ; 1A46 ; 1A4W ; 1A5G ; 1A61 ; 1ABI ; 1ABJ ; 1AD8 ; 1AE8 ; 1AFE ; 1AHT ; 1AI8 ; 1AIX ; 1AWF ; 1AWH ; 1AY6 ; 1B5G ; 1B7X ; 1BA8 ; 1BB0 ; 1BCU ; 1BHX ; 1BMM ; 1BMN ; 1BTH ; 1C1U ; 1C1V ; 1C1W ; 1C4U ; 1C4V ; 1C4Y ; 1C5L ; 1C5N ; 1C5O ; 1CA8 ; 1D3D ; 1D3P ; 1D3Q ; 1D3T ; 1D4P ; 1D6W ; 1D9I ; 1DE7 ; 1DIT ; 1DM4 ; 1DOJ ; 1DWB ; 1DWC ; 1DWD ; 1DWE ; 1DX5 ; 1E0F ; 1EB1 ; 1EOJ ; 1EOL ; 1FPC ; 1FPH ; 1G30 ; 1G32 ; 1G37 ; 1GHV ; 1GHW ; 1GHX ; 1GHY ; 1GJ4 ; 1GJ5 ; 1H8D ; 1H8I ; 1HAG ; 1HAH ; 1HAI ; 1HAO ; 1HAP ; 1HBT ; 1HDT ; 1HGT ; 1HLT ; 1HUT ; 1HXE ; 1HXF ; 1IHS ; 1IHT ; 1JMO ; 1JOU ; 1JWT ; 1K21 ; 1K22 ; 1KTS ; 1KTT ; 1LHC ; 1LHD ; 1LHE ; 1LHF ; 1LHG ; 1MH0 ; 1MU6 ; 1MU8 ; 1MUE ; 1NM6 ; 1NO9 ; 1NRN ; 1NRO ; 1NRP ; 1NRQ ; 1NRR ; 1NRS ; 1NT1 ; 1NU7 ; 1NU9 ; 1NY2 ; 1NZQ ; 1O0D ; 1O2G ; 1O5G ; 1OOK ; 1OYT ; 1P8V ; 1PPB ; 1QBV ; 1QHR ; 1QJ1 ; 1QJ6 ; 1QJ7 ; 1QUR ; 1RD3 ; 1RIW ; 1SB1 ; 1SFQ ; 1SG8 ; 1SGI ; 1SHH ; 1SL3 ; 1SR5 ; 1T4U ; 1T4V ; 1TA2 ; 1TA6 ; 1TB6 ; 1TBZ ; 1THP ; 1THR ; 1THS ; 1TMB ; 1TMT ; 1TMU ; 1TOM ; 1TQ0 ; 1TQ7 ; 1TWX ; 1UMA ; 1UVS ; 1VR1 ; 1VZQ ; 1W7G ; 1WAY ; 1WBG ; 1XM1 ; 1XMN ; 1YPE ; 1YPG ; 1YPJ ; 1YPK ; 1YPL ; 1YPM ; 1Z71 ; 1Z8I ; 1Z8J ; 1ZGI ; 1ZGV ; 1ZRB ; 2A0Q ; 2A2X ; 2A45 ; 2AFQ ; 2ANK ; 2ANM ; 2B5T ; 2BDY ; 2BVR ; 2BVS ; 2BVX ; 2BXT ; 2BXU ; 2C8W ; 2C8X ; 2C8Y ; 2C8Z ; 2C90 ; 2C93 ; 2CF8 ; 2CF9 ; 2CN0 ; 2FEQ ; 2FES ; 2GDE ; 2GP9 ; 2H9T ; 2HGT ; 2HNT ; 2HPP ; 2HPQ ; 2HWL ; 2JH0 ; 2JH5 ; 2JH6 ; 2OD3 ; 2PGB ; 2PGQ ; 2PKS ; 2PW8 ; 2R2M ; 2THF ; 2UUF ; 2UUJ ; 2UUK ; 2V3H ; 2V3O ; 2ZC9 ; 2ZDA ; 2ZDV ; 2ZF0 ; 2ZFF ; 2ZFP ; 2ZFQ ; 2ZFR ; 2ZG0 ; 2ZGB ; 2ZGX ; 2ZHE ; 2ZHF ; 2ZHQ ; 2ZHW ; 2ZI2 ; 2ZIQ ; 2ZNK ; 2ZO3 ; 3B23 ; 3B9F ; 3BEF ; 3BEI ; 3BF6 ; 3BIU ; 3BIV ; 3BV9 ; 3C1K ; 3C27 ; 3D49 ; 3DA9 ; 3DD2 ; 3DHK ; 3DT0 ; 3DUX ; 3E6P ; 3EE0 ; 3EGK ; 3EQ0 ; 3F68 ; 3GIC ; 3GIS ; 3HAT ; 3HKJ ; 3HTC ; 3JZ1 ; 3JZ2 ; 3K65 ; 3LDX ; 3LU9 ; 3NXP ; 3P17 ; 3P6Z ; 3P70 ; 3PMH ; 3PO1 ; 3QDZ ; 3QGN ; 3QLP ; 3QTO ; 3QTV ; 3QWC ; 3QX5 ; 3R3G ; 3RLW ; 3RLY ; 3RM0 ; 3RM2 ; 3RML ; 3RMM ; 3RMN ; 3RMO ; 3S7H ; 3S7K ; 3SHA ; 3SHC ; 3SI3 ; 3SI4 ; 3SQE ; 3SQH ; 3SV2 ; 3T5F ; 3TU7 ; 3U69 ; 3U8O ; 3U8R ; 3U8T ; 3U98 ; 3U9A ; 3UTU ; 3UWJ ; 3VXE ; 3VXF ; 4AX9 ; 4AYV ; 4AYY ; 4AZ2 ; 4BAH ; 4BAK ; 4BAM ; 4BAN ; 4BAO ; 4BAQ ; 4BOH ; 4CH2 ; 4CH8 ; 4DIH ; 4DII ; 4DT7 ; 4DY7 ; 4E05 ; 4E06 ; 4E7R ; 4H6S ; 4H6T ; 4HFP ; 4HTC ; 4HZH ; 4I7Y ; 4LOY ; 4LXB ; 4LZ1 ; 4LZ4 ; 4MLF ; 4NZQ ; 4O03 ; 4RKJ ; 4RKO ; 4RN6 ; 4THN ; 4UD9 ; 4UDW ; 4UE7 ; 4UEH ; 4UFD ; 4UFE ; 4UFF ; 4UFG ; 4YES ; 5A2M ; 5AF9 ; 5AFY ; 5AFZ ; 5AHG ; 5CMX ; 5DO4 ; 5E8E ; 5EDK ; 5EDM ; 5EW1 ; 5EW2 ; 5GDS ; 5GIM ; 5JDU ; 5JFD ; 5JZY ; 5L6N ; 5MJT ; 5MLS ; 5MM6 ; 5NHU ; 5TO3 ; 5Z5W ; 5Z5X ; 6BJR ; 6C2W ; 6EO6 ; 6EO7 ; 6EO8 ; 6EO9 ; 6V5T ; 7KME ; 7TPP ; 8BWW ; 8KME
• EC Number: 3.4.21.5
• Pfam ID: PF00594 ; PF00051 ; PF09396 ; PF00089
• Sequence:
  MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLEREC
  VEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHV
  NITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQE
  CSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASA
  QAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETG
  DGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYI
  DGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTEN
  DLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHP
  VCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDST
  RIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKY
  GFYTHVFRLKKWIQKVIDQFGE
• Function: Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  Complement and coagulation cascades (hsa04610)
  Platelet activation (hsa04611)
  Regulation of actin cytoskeleton (hsa04810)
  Pathogenic Escherichia coli infection (hsa05130)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Gamma-carboxylation of protein precursors (R-HSA-159740)
  Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus (R-HSA-159763)
  Removal of aminoterminal propeptides from gamma-carboxylated proteins (R-HSA-159782)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Peptide ligand-binding receptors (R-HSA-375276)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  G alpha (q) signalling events (R-HSA-416476)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Platelet Aggregation (Plug Formation) (R-HSA-76009)
  Defective factor XII causes hereditary angioedema (R-HSA-9657688)
  Defective F8 cleavage by thrombin (R-HSA-9672391)
  Regulation of Complement cascade (R-HSA-977606)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
• BioCyc Pathway: MetaCyc:HS11470-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital prothrombin deficiency	DISV48JY	Definitive	Autosomal recessive	[1]
Venous thrombosis	DISVHK7H	Definitive	Autosomal dominant	[1]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dinoprostone	DMTYOPD	Approved	Prothrombin (F2) increases the secretion of Dinoprostone.	[35]
Nitric Oxide	DM1RBYG	Approved	Prothrombin (F2) increases the abundance of Nitric Oxide.	[36]
Adenosine triphosphate	DM79F6G	Approved	Prothrombin (F2) increases the abundance of Adenosine triphosphate.	[37]
Manganese	DMKT129	Investigative	Prothrombin (F2) increases the uptake of Manganese.	[39]
adenosine diphosphate	DMFUHKP	Investigative	Prothrombin (F2) increases the abundance of adenosine diphosphate.	[37]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorotrianisene	DMSV2WZ	Withdrawn from market	Prothrombin (F2) increases the Deep vein thrombosis ADR of Chlorotrianisene.	[38]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
S-2238	DM3GS2X	Investigative	Prothrombin (F2) increases the cleavage of S-2238.	[40]

30 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 Prothrombin (F2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prothrombin (F2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Prothrombin (F2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prothrombin (F2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Prothrombin (F2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prothrombin (F2).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Prothrombin (F2).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Prothrombin (F2).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Prothrombin (F2).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Prothrombin (F2).	[12]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Prothrombin (F2).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Prothrombin (F2).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine affects the expression of Prothrombin (F2).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate increases the expression of Prothrombin (F2).	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Prothrombin (F2).	[17]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Prothrombin (F2).	[18]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the activity of Prothrombin (F2).	[19]
Colchicine	DM2POTE	Approved	Colchicine affects the activity of Prothrombin (F2).	[20]
Ardeparin	DMYRX8B	Approved	Ardeparin increases the expression of Prothrombin (F2).	[21]
Warfarin	DMJYCVW	Approved	Warfarin decreases the expression of Prothrombin (F2).	[23]
Phytonadione	DM8HDOL	Approved	Phytonadione increases the expression of Prothrombin (F2).	[24]
Eptifibatide	DMQXTJS	Approved	Eptifibatide increases the expression of Prothrombin (F2).	[25]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Prothrombin (F2).	[26]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the activity of Prothrombin (F2).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prothrombin (F2).	[28]
Nimesulide	DMR1NMD	Terminated	Nimesulide decreases the activity of Prothrombin (F2).	[30]
NS398	DMINUWH	Terminated	NS398 decreases the activity of Prothrombin (F2).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Prothrombin (F2).	[31]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Prothrombin (F2).	[32]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid decreases the activity of Prothrombin (F2).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the cleavage of Prothrombin (F2).	[6]
Aspirin	DM672AH	Approved	Aspirin affects the cleavage of Prothrombin (F2).	[15]
Ximelagatran	DMABRJL	Withdrawn from market	Ximelagatran decreases the cleavage of Prothrombin (F2).	[29]
STO609	DMZSOG2	Investigative	STO609 decreases the response to substance of Prothrombin (F2).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Prothrombin (F2).	[22]

References

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