Details of the Drug Combination

General Information of Drug Combination (ID: DC8XX7S)

• Drug Combination Name: Tofacitinib + Hydroxychloroquine
• Indication: Pneumonitis, Interstitial; Status: Phase 2 [1]
• Component Drugs:
  Tofacitinib (DMBS370): Small molecular drug
  Hydroxychloroquine (DMSIVND): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tofacitinib

Disease Entry	ICD 11	Status	REF
Rheumatoid arthritis	FA20	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[3]

Tofacitinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 3 (JAK-3)	TTT7PJU	JAK3_HUMAN	Modulator	[9]

Tofacitinib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]

Tofacitinib Interacts with 44 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Decreases Expression	[8]
C-X-C motif chemokine 11 (CXCL11)	OT353XE3	CXL11_HUMAN	Decreases Expression	[11]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Decreases Expression	[8]
C-X-C motif chemokine 13 (CXCL13)	OT2AT4N8	CXL13_HUMAN	Decreases Expression	[12]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Decreases Activity	[7]
Cytochrome c oxidase subunit 1 (COX1)	OTG3O9BN	COX1_HUMAN	Increases Expression	[8]
2'-5'-oligoadenylate synthase 1 (OAS1)	OT8ZLOCY	OAS1_HUMAN	Decreases Expression	[8]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Decreases Expression	[11]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[12]
Ubiquitin-like protein ISG15 (ISG15)	OT53QQ7N	ISG15_HUMAN	Decreases Expression	[8]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[11]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Increases Expression	[8]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Decreases Expression	[12]
Keratin, type I cytoskeletal 16 (KRT16)	OTGA0EQN	K1C16_HUMAN	Decreases Expression	[13]
Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)	OTXOQDSG	IFIT1_HUMAN	Decreases Expression	[11]
Interferon-induced transmembrane protein 1 (IFITM1)	OTECO1G8	IFM1_HUMAN	Decreases Expression	[8]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[12]
Interferon-induced GTP-binding protein Mx1 (MX1)	OT6X8G5T	MX1_HUMAN	Decreases Expression	[8]
Interferon-induced GTP-binding protein Mx2 (MX2)	OT05NF37	MX2_HUMAN	Decreases Expression	[8]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Decreases Activity	[14]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[7]
2'-5'-oligoadenylate synthase 2 (OAS2)	OT64CCTM	OAS2_HUMAN	Decreases Expression	[8]
Succinate dehydrogenase flavoprotein subunit, mitochondrial (SDHA)	OTOJ8QFF	SDHA_HUMAN	Increases Expression	[8]
Interferon alpha-inducible protein 27, mitochondrial (IFI27)	OTI2XGIT	IFI27_HUMAN	Decreases Expression	[8]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Activity	[15]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Decreases Expression	[11]
Signal transducer and activator of transcription 5A (STAT5A)	OTBSJGN3	STA5A_HUMAN	Decreases Phosphorylation	[16]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Decreases Expression	[8]
Signal transducer and activator of transcription 5B (STAT5B)	OTZVPEBT	STA5B_HUMAN	Decreases Phosphorylation	[16]
Interferon-induced 35 kDa protein (IFI35)	OTV9RZ53	IN35_HUMAN	Decreases Expression	[8]
Interferon regulatory factor 9 (IRF9)	OTK4MYQJ	IRF9_HUMAN	Decreases Expression	[8]
AMP deaminase 2 (AMPD2)	OTBS30JU	AMPD2_HUMAN	Decreases Expression	[17]
C-X-C motif chemokine 9 (CXCL9)	OTMFVZKZ	CXCL9_HUMAN	Decreases Expression	[11]
Bone marrow stromal antigen 2 (BST2)	OTU4LCJV	BST2_HUMAN	Decreases Expression	[8]
Sonic hedgehog protein (SHH)	OTOG2BXF	SHH_HUMAN	Increases Expression	[8]
Secreted frizzled-related protein 5 (SFRP5)	OTLCVVSH	SFRP5_HUMAN	Increases Expression	[8]
Interferon-induced protein 44 (IFI44)	OTOKSZVA	IFI44_HUMAN	Decreases Expression	[8]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Decreases Expression	[8]
Interferon regulatory factor 7 (IRF7)	OTC1A2PQ	IRF7_HUMAN	Decreases Expression	[11]
Kelch-like protein 31 (KLHL31)	OTXZVWDL	KLH31_HUMAN	Increases Expression	[8]
Histone-lysine N-methyltransferase PRDM16 (PRDM16)	OT0BGA27	PRD16_HUMAN	Increases Expression	[8]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Metabolism	[18]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Metabolism	[19]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Metabolism	[18]

Indication(s) of Hydroxychloroquine

Disease Entry	ICD 11	Status	REF
Chronic renal failure	GB61.Z	Approved	[4]
Malaria	1F40-1F45	Approved	[5]
Plasmodium falciparum malaria	1F40	Approved	[4]
Plasmodium malariae malaria	N.A.	Approved	[4]
Plasmodium ovale malaria	N.A.	Approved	[4]
Systemic lupus erythematosus	4A40.0	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Colon cancer	2B90.Z	Investigative	[4]

Hydroxychloroquine Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN pH-dependent viral fusion/replication (pH-DVF/R)	TTD16BI	N.A.	Inhibitor	[20]
HUMAN glycosylation of host receptor (GHR)	TTZGK1R	N.A.	Inhibitor	[20]
Toll-like receptor 7 (TLR7)	TTRJ1K4	TLR7_HUMAN	Antagonist	[21]
HUMAN toll-like receptor 7/9 signalling pathway (TLR7/9 pathway)	TT3A1EZ	N.A.	Inhibitor	[22]

Hydroxychloroquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[23]

Hydroxychloroquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[24]

Hydroxychloroquine Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[25]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Increases Expression	[26]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[27]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[26]
Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1)	OT4TMERS	NFAC1_HUMAN	Affects Expression	[28]
Claudin-1 (CLDN1)	OT27KV99	CLD1_HUMAN	Increases Expression	[29]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[26]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Increases Expression	[26]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Affects Expression	[30]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Affects Expression	[30]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[26]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Affects Localization	[31]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[32]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[33]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[33]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Degradation	[26]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[28]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[27]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Expression	[26]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Activity	[31]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Increases Expression	[26]
Nuclear factor of activated T-cells, cytoplasmic 2 (NFATC2)	OTK5T6HZ	NFAC2_HUMAN	Affects Localization	[28]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[34]
Interferon regulatory factor 3 (IRF3)	OT81U8ME	IRF3_HUMAN	Increases Phosphorylation	[26]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Increases Expression	[29]
Mitochondrial antiviral-signaling protein (MAVS)	OTTQ0J64	MAVS_HUMAN	Increases Expression	[26]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Increases Expression	[26]
Interferon-induced helicase C domain-containing protein 1 (IFIH1)	OTZA2AHA	IFIH1_HUMAN	Increases Expression	[26]
Toll-like receptor 9 (TLR9)	OTFZ45HX	TLR9_HUMAN	Decreases Expression	[35]
7-dehydrocholesterol reductase (DHCR7)	OTLILBUI	DHCR7_HUMAN	Affects Expression	[30]

References

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• [2] 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: 5677).
• [3] ClinicalTrials.gov (NCT04332042) TOFAcitinib in SARS-CoV2 Pneumonia. U.S. National Institutes of Health.
• [4] Hydroxychloroquine FDA Label
• [5] 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: 7198).
• [6] ClinicalTrials.gov (NCT04341727) Hydroxychloroquine,Hydroxychloroquine,Azithromycin in the Treatment of SARS CoV-2 Infection (WU352). U.S. National Institutes of Health.
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