Details of the Drug Combination

General Information of Drug Combination (ID: DC9D5SW)

Drug Combination Name

Trihexyphenidyl Dronedarone

Indication

Disease Entry	Status	REF
Chronic myelogenous leukemia	Investigative	[1]

Component Drugs

Trihexyphenidyl DMB19L8

Dronedarone DMA8FS5

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: KBM-7

Zero Interaction Potency (ZIP) Score: 0.79

Bliss Independence Score: 0.79

Loewe Additivity Score: 14.8

LHighest Single Agent (HSA) Score: 14.81

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Trihexyphenidyl

Disease Entry	ICD 11	Status	REF
Dystonia	8A02	Approved	[2]
Parkinson disease	8A00.0	Approved	[2]
Parkinsonian disorder	N.A.	Approved	[3]
Postencephalitic Parkinson disease	N.A.	Approved	[3]
Obesity	5B81	Investigative	[4]

Trihexyphenidyl Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Muscarinic acetylcholine receptor M1 (CHRM1)	TTZ9SOR	ACM1_HUMAN	Antagonist	[6]
Adrenergic receptor beta-3 (ADRB3)	TTMXGCW	ADRB3_HUMAN	Agonist	[4]
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Trihexyphenidyl Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[7]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[7]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[7]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[7]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[7]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[7]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[7]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[7]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Increases Expression	[7]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[7]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[7]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[7]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Increases Response To Substance	[8]
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⏷ Show the Full List of 13 DOT(s)

Indication(s) of Dronedarone

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[5]
Atrial fibrillation	BC81.3	Withdrawn from market	[5]

Dronedarone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated potassium channel Kv1.5 (KCNA5)	TTW0CMT	KCNA5_HUMAN	Blocker	[9]
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Inhibitor	[10]
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Dronedarone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[13]
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Dronedarone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Response To Substance	[14]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Response To Substance	[14]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Response To Substance	[14]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[15]
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Decreases Expression	[14]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[14]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[14]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[14]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[14]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[15]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[15]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[14]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[16]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[17]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Metabolism	[14]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[14]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Metabolism	[14]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Increases Metabolism	[14]
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⏷ Show the Full List of 21 DOT(s)

References

1	Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
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: 7315).
3	Trihexyphenidyl FDA Label
4	Obesity: pathophysiology and clinical management. Curr Med Chem. 2009;16(4):506-21.
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: 7465).
6	The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic dr... Psychopharmacology (Berl). 2009 Apr;203(2):295-301.
7	An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
8	Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly. Am J Geriatr Psychiatry. 2008 Feb;16(2):116-24. doi: 10.1097/JGP.0b013e31815aff75.
9	New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.
10	Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
11	Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf. 2012 Nov;11(6):1023-45.
12	Effect of dronedarone on the pharmacokinetics of carvedilol following oral administration to rats. Eur J Pharm Sci. 2018 Jan 1;111:13-19.
13	Inactivation of human cytochrome P450 3A4 and 3A5 by dronedarone and N-desbutyl dronedarone. Mol Pharmacol. 2016 Jan;89(1):1-13.
14	The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. Arch Toxicol. 2018 Jun;92(6):1969-1981. doi: 10.1007/s00204-018-2196-x. Epub 2018 Apr 3.
15	Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone. Toxicol Sci. 2013 Feb;131(2):480-90. doi: 10.1093/toxsci/kfs298. Epub 2012 Nov 7.
16	Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet. 2002;17(4):374-7. doi: 10.2133/dmpk.17.374.
17	Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.