Details of the Drug Combination

General Information of Drug Combination (ID: DCC2RVR)

• Drug Combination Name: Propranolol + Naltrexone
• Indication: Advanced Melanoma; Status: Phase 1 [1]
• Component Drugs:
  Propranolol (DM79NTF): Small molecular drug
  Naltrexone (DMUL45H): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Propranolol

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Atrial fibrillation	BC81.3	Approved	[2]
Cocaine addiction	6C45.2	Approved	[2]
Hemangioma	2E81-2F2Y	Approved	[2]
Migraine	8A80	Approved	[3]
Respiratory papillomatosis	2F00.1	Investigative	[2]

Propranolol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Antagonist	[10]

Propranolol Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[12]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[12]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[12]

Propranolol Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[17]
Dimethylaniline oxidase 2 (FMO2)	DEIASEZ	FMO2_HUMAN	Metabolism	[18]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[19]

Propranolol Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Oxidation	[20]
Flavin-containing monooxygenase 2 (FMO2)	OTUJUL9S	FMO2_HUMAN	Increases Oxidation	[18]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[21]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[22]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[23]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Expression	[24]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Expression	[25]
G protein-activated inward rectifier potassium channel 1 (KCNJ3)	OTHQG16J	KCNJ3_HUMAN	Increases Expression	[24]
ADP-ribosylation factor 6 (ARF6)	OTVV7KJO	ARF6_HUMAN	Affects Localization	[26]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[27]
Potassium voltage-gated channel subfamily E member 1 (KCNE1)	OTZNQUW9	KCNE1_HUMAN	Increases ADR	[27]

Indication(s) of Naltrexone

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[4]
Chronic alcoholism	6C40.2Z	Approved	[5]
Crohn disease	DD70	Approved	[6]
Gastroparesis	DA41.00	Approved	[6]
Inflammatory bowel disease	DD72	Approved	[6]
Obesity	5B81	Approved	[6]
Ulcerative colitis	DD71	Approved	[6]
Human immunodeficiency virus infection	1C62	Phase 4	[7]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[8]
Chronic pain	MG30	Investigative	[6]

Naltrexone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Antagonist	[28]

Naltrexone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[29]

Naltrexone Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[30]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[30]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Affects Response To Substance	[28]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[28]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[31]
Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)	OTAOZIGX	GBRB2_HUMAN	Affects Response To Substance	[32]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[32]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Response To Substance	[32]

References

• [1] ClinicalTrials.gov (NCT05968690) Naltrexone and Propranolol Combined With Immunotherapy
• [2] Propranolol FDA Label
• [3] 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: 7596).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074918.
• [6] Naltrexone FDA Label
• [7] 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: 1639).
• [8] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
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• [25] Propranolol inhibits proliferation and invasion of hemangioma-derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway. Chem Biol Interact. 2018 Oct 1;294:28-33. doi: 10.1016/j.cbi.2018.08.018. Epub 2018 Aug 18.
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• [30] Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients. J Clin Endocrinol Metab. 1995 May;80(5):1739-42. doi: 10.1210/jcem.80.5.7745028.
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