Details of the Drug Combination

General Information of Drug Combination (ID: DCI7PS8)

• Drug Combination Name: 3,7,3',4'-TETRAHYDROXYFLAVONE + Losartan
• Indication: Osteoarthritis, Knee; Status: Phase 1 [1]
• Component Drugs:
  3,7,3',4'-TETRAHYDROXYFLAVONE (DMES906): Small molecular drug
  Losartan (DM72JXH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of 3,7,3',4'-TETRAHYDROXYFLAVONE

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

3,7,3',4'-TETRAHYDROXYFLAVONE Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium Beta-hydroxyacyl-ACP dehydratase (Malaria FabZ)	TTHPFTS	Q965D7_PLAFA	Inhibitor	[8]
Fatty acid synthase (FASN)	TT7AOUD	FAS_HUMAN	Inhibitor	[8]
Plasmodium Enoyl-ACP reductase (Malaria fabI)	TTNX2CS	Q965D5_PLAFA	Inhibitor	[8]
Plasmodium Oxoacyl-[acyl-carrier protein] reductase (Malaria fabG)	TTBE4IR	Q965D6_PLAFA	Inhibitor	[8]
Cyclin-dependent kinase 6 (CDK6)	TTO0FDJ	CDK6_HUMAN	Inhibitor	[2]

3,7,3',4'-TETRAHYDROXYFLAVONE Interacts with 49 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[9]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Expression	[10]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Expression	[11]
Prominin-1 (PROM1)	OTBHV8NX	PROM1_HUMAN	Decreases Expression	[6]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Localization	[11]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Expression	[11]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[12]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[13]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[11]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Decreases Expression	[14]
Calpain-1 catalytic subunit (CAPN1)	OTK6OQZR	CAN1_HUMAN	Increases Expression	[11]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Activity	[16]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Decreases Expression	[14]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[11]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[11]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[6]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[12]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[6]
Calpain-2 catalytic subunit (CAPN2)	OTIAPE5J	CAN2_HUMAN	Increases Expression	[11]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[11]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[6]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[11]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Decreases Expression	[17]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[11]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[18]
CCN family member 2 (CCN2)	OTC39NSU	CCN2_HUMAN	Decreases Expression	[19]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[11]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[6]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[11]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[12]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[18]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[12]
Caspase-4 (CASP4)	OTVQTV1L	CASP4_HUMAN	Increases Expression	[11]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[11]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[12]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[19]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[19]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[20]
Endonuclease G, mitochondrial (ENDOG)	OT5IM7B3	NUCG_HUMAN	Increases Localization	[11]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[18]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[15]
Inactive caspase-12 (CASP12)	OTY2W6FG	CASPC_HUMAN	Increases Expression	[11]
Type II iodothyronine deiodinase (DIO2)	OTGPNSLH	IOD2_HUMAN	Increases Activity	[21]
Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B)	OTT2ZGSR	ATF6B_HUMAN	Increases Expression	[11]
Serine/threonine-protein kinase LATS2 (LATS2)	OT6XO8JP	LATS2_HUMAN	Increases Phosphorylation	[19]
Mitogen-activated protein kinase kinase kinase 20 (MAP3K20)	OT0ALMEG	M3K20_HUMAN	Increases Expression	[19]

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	[22]
HUMAN type-1 angiotensin II receptor (AGTR1)	TTPKMXQ	AGTR1_HUMAN	Blocker	[23]

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	[24]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[25]

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	[26]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[27]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[26]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[28]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[29]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[29]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[29]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[29]

Losartan Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases ADR	[30]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases ADR	[30]

References

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• [2] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [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.
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• [13] Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochem Biophys Res Commun. 2006 Feb 3;340(1):1-7. doi: 10.1016/j.bbrc.2005.11.157. Epub 2005 Dec 6.
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• [23] Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020 Apr 3.
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