Details of the Drug Combination

General Information of Drug Combination (ID: DCFDV8J)

• Drug Combination Name: THIOCTIC ACID + Losartan
• Indication: Diabetic nephropathy; Status: Phase 1 [1]
• Component Drugs:
  THIOCTIC ACID (DMNFCXW): Small molecular drug
  Losartan (DM72JXH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of THIOCTIC ACID

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

THIOCTIC ACID Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acetylcholinesterase (AChE)	TT1RS9F	ACES_HUMAN	Inhibitor	[7]
Prostaglandin G/H synthase 2 (COX-2)	TTVKILB	PGH2_HUMAN	Inhibitor	[2]

THIOCTIC ACID Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Increases Expression	[8]
Epididymal secretory glutathione peroxidase (GPX5)	OTQMMNNT	GPX5_HUMAN	Increases Expression	[9]
Glutathione peroxidase 3 (GPX3)	OT6PK94R	GPX3_HUMAN	Increases Expression	[9]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Increases Expression	[10]

Indication(s) of Losartan

Disease Entry	ICD 11	Status	REF
Diabetic kidney disease	GB61.Z	Approved	[3]
Hypertension	BA00-BA04	Approved	[4]
Prediabetes syndrome	N.A.	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[5]

Losartan Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[11]
HUMAN type-1 angiotensin II receptor (AGTR1)	TTPKMXQ	AGTR1_HUMAN	Blocker	[12]

Losartan Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[14]

Losartan Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[16]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[17]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[18]

References

• [1] Therapeutic approaches to diabetic nephropathy--beyond the RAS. Nat Rev Nephrol. 2014 Jun;10(6):325-46.
• [2] Investigations concerning the COX/5-LOX inhibiting and hydroxyl radical scavenging potencies of novel 4,5-diaryl isoselenazoles. Eur J Med Chem. 2008 Jun;43(6):1152-9.
• [3] Losartan 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: 590).
• [5] ClinicalTrials.gov (NCT04343001) Coronavirus Response - Active Support for Hospitalised Covid-19 Patients. U.S. National Institutes of Health.
• [6] Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors. Free Radic Biol Med. 2011 Mar 15;50(6):689-99.
• [7] Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008 Feb 14;51(3):347-72.
• [8] HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and THP-1 cell line: role of the Keap1/Nrf2 pathway. Toxicol Sci. 2009 Feb;107(2):451-60.
• [9] Cytoprotective effect of alpha-lipoic acid on paraquat-exposed human bronchial epithelial cells via activation of nuclear factor erythroid related factor-2 pathway. Biol Pharm Bull. 2013;36(5):802-11.
• [10] Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease. J Cell Mol Med. 2010 Jan;14(1-2):215-25. doi: 10.1111/j.1582-4934.2008.00390.x.
• [11] Radioligand binding assays: application of [(125)I]angiotensin II receptor binding. Methods Mol Biol. 2009;552:131-41.
• [12] Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020 Apr 3.
• [13] Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers. Br J Pharmacol. 2000 Mar;129(6):1235-43.
• [14] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [15] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [16] The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol. 2008 Sep 15;76(6):763-72.
• [17] Drug-drug interaction between losartan and paclitaxel in human liver microsomes with different CYP2C8 genotypes. Basic Clin Pharmacol Toxicol. 2015 Jun;116(6):493-8.
• [18] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.