Details of the Drug Combination

General Information of Drug Combination (ID: DC7UJ5S)

• Drug Combination Name: Remdesivir + Baricitinib
• Indication: COVID-19; Status: Phase 3 [1]
• Component Drugs:
  Remdesivir (DMBFZ6L): Small molecular drug
  Baricitinib (DM4ONW5): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Remdesivir

Disease Entry	ICD 11	Status	REF
Coronavirus Disease 2019 (COVID-19)	1D6Y	Approved	[2]
Ebola virus infection	1D60.0	Phase 1	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[4]

Remdesivir Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV RNA-directed RNA polymerase (RdRp)	TTOA6YT	R1AB_CVEMC (4378-5310)	Inhibitor	[4]
SARS-CoV RNA-directed RNA polymerase (RdRp)	TTKXI53	R1AB_CVHSA (4370-5301)	Inhibitor	[4]
COVID-19 RNA-directed RNA polymerase (RdRp)	TTV1095	R1AB_SARS2 (4393-5324)	Inhibitor	[7]
COVID-19 RNA-directed RNA polymerase (RdRp)	TTV1095	R1AB_SARS2 (4393-5324)	Inhibitor	[2]

Remdesivir Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[8]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[8]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Expression	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[8]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[8]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[8]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Decreases Expression	[8]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[8]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[8]
Lysosomal protective protein (CTSA)	OT167UBM	PPGB_HUMAN	Increases Hydrolysis	[9]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Increases Hydrolysis	[9]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Hydrolysis	[9]
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Increases Hydrolysis	[9]

Indication(s) of Baricitinib

Disease Entry	ICD 11	Status	REF
Rheumatoid arthritis	FA20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]

Baricitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN cyclin G-associated kinase (GAK)	TT0AGBL	GAK_HUMAN	Inhibitor	[10]
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[11]
Tyrosine-protein kinase (PTK)	TTJSQEF	NOUNIPROTAC	Inhibitor	[5]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[11]
HUMAN adaptor-associated kinase 1 (AAK1)	TTN9A16	AAK1_HUMAN	Inhibitor	[10]

Baricitinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[13]

Baricitinib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]

Baricitinib Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cyclin-G-associated kinase (GAK)	OTLM5H4P	GAK_HUMAN	Decreases Activity	[15]
AP2-associated protein kinase 1 (AAK1)	OTK9B9QT	AAK1_HUMAN	Decreases Activity	[15]

References

• [1] ClinicalTrials.gov (NCT04401579) Adaptive COVID-19 Treatment Trial 2 (ACTT-2)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020 Jan 10;11(1):222.
• [5] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [6] ClinicalTrials.gov (NCT04345289) Efficacy and Safety of Novel Treatment Options for Adults With COVID-19 Pneumonia. U.S. National Institutes of Health.
• [7] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
• [8] An in vitro study on anti-carcinogenic effect of remdesivir in human ovarian cancer cells via generation of reactive oxygen species. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221089257. doi: 10.1177/09603271221089257.
• [9] Human carboxylesterase 1A plays a predominant role in the hydrolytic activation of remdesivir in humans. Chem Biol Interact. 2022 Jan 5;351:109744. doi: 10.1016/j.cbi.2021.109744. Epub 2021 Nov 11.
• [10] Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31.
• [11] Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs. 2014 Aug;23(8):1067-77.
• [12] Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib. Clin Transl Sci. 2017 Nov;10(6):509-519.
• [13] Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e01201-17.
• [14] FDA label of Baricitinib. The 2020 official website of the U.S. Food and Drug Administration.
• [15] COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020 Apr;20(4):400-402. doi: 10.1016/S1473-3099(20)30132-8. Epub 2020 Feb 27.