Details of the Drug Combination

General Information of Drug Combination (ID: DCIR0KC)

• Drug Combination Name: Tiagabine + Spironolactone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Tiagabine (DMKSQG0): Small molecular drug
  Spironolactone (DM2AQ5N): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 9.09
  Bliss Independence Score: 9.09
  Loewe Additivity Score: 11.09
  LHighest Single Agent (HSA) Score: 11.1

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tiagabine

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[2]
Anxiety disorder	6B00-6B0Z	Phase 2	[2]

Tiagabine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gamma-aminobutyric acid uptake (GABAU)	TTV9MQG	NOUNIPROTAC	Inhibitor	[6]
GABA transporter GAT-1 (SLC6A1)	TTPRKM0	SC6A1_HUMAN	Inhibitor	[7]

Tiagabine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[9]

Tiagabine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[10]
Sodium- and chloride-dependent GABA transporter 1 (SLC6A1)	OTLCJJF3	SC6A1_HUMAN	Decreases Activity	[11]

Indication(s) of Spironolactone

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[3]
Congestive heart failure	BD10	Approved	[4]
Edema	MG29	Approved	[3]
Hyperaldosteronism	5A72	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[5]

Spironolactone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Modulator	[12]

Spironolactone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[13]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Serine/threonine-protein kinase Sgk1 (SGK1)	OT301T1U	SGK1_HUMAN	Increases Expression	[16]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[17]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[18]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[19]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[20]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[19]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[21]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Decreases Expression	[17]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[22]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[23]
Myb-related protein A (MYBL1)	OTBJMC2P	MYBA_HUMAN	Increases Expression	[16]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Binding	[24]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[25]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[25]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Increases Expression	[16]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Response To Substance	[26]
Serum paraoxonase/lactonase 3 (PON3)	OT80W9TA	PON3_HUMAN	Increases Hydrolysis	[27]

References

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• [3] Spironolactone FDA Label
• [4] 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: 2875).
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• [22] Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells. Toxicology. 2011 Jul 11;285(1-2):18-24. doi: 10.1016/j.tox.2011.03.015. Epub 2011 Apr 1.
• [23] The human mineralocorticoid receptor only partially differentiates between different ligands after expression in fission yeast. FEMS Yeast Res. 2005 Apr;5(6-7):627-33. doi: 10.1016/j.femsyr.2004.12.007.
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• [27] Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.