Details of the Drug Combination

General Information of Drug Combination (ID: DCADO04)

• Drug Combination Name: Chlorthalidone + Lisinopril
• Indication: Hypertension; Status: Phase 4 [1]
• Component Drugs:
  Chlorthalidone (DM4DMBT): Small molecular drug
  Lisinopril (DMUOK4C): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Chlorthalidone

Disease Entry	ICD 11	Status	REF
Edema	MG29	Approved	[2]
Hypertension	BA00-BA04	Approved	[2]
High blood pressure	BA00	Investigative	[3]

Chlorthalidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Solute carrier family 12 member 1 (SLC12A1)	TTS087L	S12A1_HUMAN	Blocker	[7]

Chlorthalidone Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[8]

Indication(s) of Lisinopril

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Myocardial infarction	BA41-BA43	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[6]
High blood pressure	BA00	Investigative	[4]

Lisinopril Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[9]
HUMAN angiotensin-converting enzyme (ACE)	TTGFNPD	ACE_HUMAN	Inhibitor	[6]

Lisinopril Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[10]

Lisinopril Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Decreases Activity	[11]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[12]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[13]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[13]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Secretion	[14]
Insulin-like growth factor-binding protein 1 (IGFBP1)	OT6UQV2K	IBP1_HUMAN	Increases Expression	[15]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[16]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[17]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Hypertension	DCM2S0Z	N. A.	Phase 4	[1]

References

• [1] ClinicalTrials.gov (NCT02847338) Comparison of Optimal Hypertension Regimens
• [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: 7147).
• [3] Chlorthalidone FDA Label
• [4] Lisinopril FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc. 2020 Apr 7;9(7):e016219.
• [7] The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol. 2004 Mar 31;217(1-2):45-52.
• [8] Detection of low-renin hypertension; evaluation of out-patient renin-stimulating methods. Clin Sci Mol Med. 1975 Feb;48(2):91-6. doi: 10.1042/cs0480091.
• [9] Involvement of vascular angiotensin II-forming enzymes in the progression of aortic abdominal aneurysms in angiotensin II- infused ApoE-deficient m... J Atheroscler Thromb. 2009 Jun;16(3):164-71.
• [10] Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharm Res. 2007 Apr;30(4):507-18.
• [11] Targeted catalytic inactivation of angiotensin converting enzyme by lisinopril-coupled transition-metal chelates. J Am Chem Soc. 2012 Feb 22;134(7):3396-410. doi: 10.1021/ja208791f. Epub 2012 Feb 10.
• [12] Hemodynamic responses to converting enzyme inhibition in patients with renal disease. Am J Hypertens. 1989 Aug;2(8):599-603. doi: 10.1093/ajh/2.8.599.
• [13] Effects of lisinopril on cardiorespiratory, neuroendocrine, and renal function in patients with asymptomatic left ventricular dysfunction. Br Heart J. 1993 Jun;69(6):512-5. doi: 10.1136/hrt.69.6.512.
• [14] Different effects of angiotensin converting enzyme inhibitors on endothelin-1 and nitric oxide balance in human vascular endothelial cells: evidence of an oxidant-sensitive pathway. Mediators Inflamm. 2008;2008:305087. doi: 10.1155/2008/305087. Epub 2008 Dec 1.
• [15] Tissue availability of insulin-like growth factor I is inversely related to insulin resistance in essential hypertension: effects of angiotensin converting enzyme inhibition. J Hypertens. 1998 Jun;16(6):863-70. doi: 10.1097/00004872-199816060-00018.
• [16] Reduced bcl-2 concentrations in hypertensive patients after lisinopril or nifedipine administration. Am J Hypertens. 1999 Jan;12(1 Pt 1):73-5. doi: 10.1016/s0895-7061(98)00217-9.
• [17] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [18] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.