Details of the Drug Combination

General Information of Drug Combination (ID: DCDR4AC)

• Drug Combination Name: Sildenafil + Acetylcholine
• Indication: Microvascular Coronary Artery Disease; Status: Phase 1 [1]
• Component Drugs:
  Sildenafil (DM4YDAJ): Small molecular drug
  Acetylcholine (DMDF79Z): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sildenafil

Disease Entry	ICD 11	Status	REF
Alveolar capillary dysplasia with misalignment of pulmonary veins	N.A.	Approved	[2]
Erectile dysfunction	HA01.1	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Respiratory failure	CB41	Investigative	[2]

Sildenafil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN phosphodiesterase type 5 (PDE5)	TTRYFSB	PDE5A_HUMAN	Inhibitor	[6]

Sildenafil Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3)	OTA6HYBA	GBB3_HUMAN	Increases Response	[7]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Increases Response	[8]

Indication(s) of Acetylcholine

Disease Entry	ICD 11	Status	REF
Cataract	9B10	Approved	[5]

Acetylcholine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Muscarinic acetylcholine receptor (CHRM)	TTOXS3C	NOUNIPROTAC	Agonist	[9]

Acetylcholine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[10]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[11]
Vesicular acetylcholine transporter (SLC18A3)	DT3T2K0	VACHT_HUMAN	Substrate	[12]
Choline transporter-like protein 4 (SLC44A4)	DT8KXR9	CTL4_HUMAN	Substrate	[13]

Acetylcholine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Acetylcholinesterase (ACHE)	DEQ2BAJ	ACES_HUMAN	Metabolism	[14]

Acetylcholine Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Increases Hydrolysis	[15]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Increases Secretion	[16]
Muscarinic acetylcholine receptor M2 (CHRM2)	OTUMZ2WR	ACM2_HUMAN	Affects Binding	[17]
Muscarinic acetylcholine receptor M4 (CHRM4)	OTF0F0FF	ACM4_HUMAN	Affects Binding	[17]
Muscarinic acetylcholine receptor M5 (CHRM5)	OTNQRQGG	ACM5_HUMAN	Increases Activity	[18]
Muscarinic acetylcholine receptor M1 (CHRM1)	OTKW3E6B	ACM1_HUMAN	Increases Activity	[19]
Muscarinic acetylcholine receptor M3 (CHRM3)	OTKSD095	ACM3_HUMAN	Increases Activity	[20]
Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7)	OTBUSUTE	ACHA7_HUMAN	Increases Activity	[21]
Interleukin-1 receptor antagonist protein (IL1RN)	OT308CBE	IL1RA_HUMAN	Affects Response To Substance	[22]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Affects Response To Substance	[23]
Secreted Ly-6/uPAR-related protein 1 (SLURP1)	OT89YD2E	SLUR1_HUMAN	Increases Abundance	[24]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Increases Response To Substance	[25]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Decreases Response To Substance	[26]
Interleukin-5 receptor subunit alpha (IL5RA)	OTMSLUG9	IL5RA_HUMAN	Increases Response To Substance	[25]
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Increases Degradation	[27]
Lipoprotein lipase (LPL)	OTTW0267	LIPL_HUMAN	Affects Response To Substance	[28]
Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2)	OTVQQSMK	ACHA2_HUMAN	Affects Response To Substance	[29]

References

• [1] ClinicalTrials.gov (NCT03462017) Pharmacodynamic Study to Assess the Effects of Repeated Dosing of SAR247799 on Endothelial Function in Patients With Type 2 Diabetes Mellitus
• [2] Sildenafil FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 206401.
• [4] ClinicalTrials.gov (NCT04304313) A Pilot Study of Sildenafil in COVID-19. U.S. National Institutes of Health.
• [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: 294).
• [6] Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005 Feb;79(3):1966-9. doi: 10.1128/JVI.79.3.1966-1969.2005.
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• [8] ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction. Urology. 2003 Jul;62(1):152-7. doi: 10.1016/s0090-4295(03)00137-7.
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• [13] Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis. J Neurochem. 2013 Aug;126(4):451-61.
• [14] How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [15] Monitoring the reaction of carbachol with acetylcholinesterase by thioflavin T fluorescence and acetylthiocholine hydrolysis. Chem Biol Interact. 2008 Sep 25;175(1-3):235-41. doi: 10.1016/j.cbi.2008.06.002. Epub 2008 Jun 17.
• [16] Acetylcholine and nicotine stimulate the release of granulocyte-macrophage colony stimulating factor from cultured human bronchial epithelial cells. Naunyn Schmiedebergs Arch Pharmacol. 1998 Apr;357(4):472-5. doi: 10.1007/pl00005195.
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• [18] Characterizing fucoxanthin as a selective dopamine D(3)/D(4) receptor agonist: Relevance to Parkinson's disease. Chem Biol Interact. 2019 Sep 1;310:108757. doi: 10.1016/j.cbi.2019.108757. Epub 2019 Jul 16.
• [19] Regional differences in functional receptor distribution and calcium mobilization in the intact human lens. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2355-63.
• [20] Assessment of false transmitters as treatments for nerve agent poisoning. Toxicol Lett. 2020 Mar 15;321:21-31. doi: 10.1016/j.toxlet.2019.12.010. Epub 2019 Dec 9.
• [21] Gain of function mutation of the alpha7 nicotinic receptor: distinct pharmacology of the human alpha7V274T variant. Eur J Pharmacol. 1999 Feb 5;366(2-3):301-8. doi: 10.1016/s0014-2999(98)00909-1.
• [22] Autocrine interaction between IL-5 and IL-1beta mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest. 1999 Sep;104(5):657-67. doi: 10.1172/JCI7137.
• [23] Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Circulation. 2003 Sep 23;108(12):1425-7. doi: 10.1161/01.CIR.0000091255.63645.98. Epub 2003 Sep 15.
• [24] SLURP-1, an endogenous 7 nicotinic acetylcholine receptor allosteric ligand, is expressed in CD205(+) dendritic cells in human tonsils and potentiates lymphocytic cholinergic activity. J Neuroimmunol. 2014 Feb 15;267(1-2):43-9. doi: 10.1016/j.jneuroim.2013.12.003. Epub 2013 Dec 11.
• [25] The IL-5 receptor on human bronchus selectively primes for hyperresponsiveness. J Allergy Clin Immunol. 2002 Mar;109(3):404-9. doi: 10.1067/mai.2002.122459.
• [26] Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction. J Am Coll Cardiol. 2003 Feb 19;41(4):539-45. doi: 10.1016/s0735-1097(02)02866-8.
• [27] Interaction between CYP19 aromatase and butyrylcholinesterase genes increases Alzheimer's disease risk. Dement Geriatr Cogn Disord. 2005;20(2-3):153-7. doi: 10.1159/000087065. Epub 2005 Jul 13.
• [28] Tissue-specific expression of human lipoprotein lipase in the vascular system affects vascular reactivity in transgenic mice. Br J Pharmacol. 2002 Jan;135(1):143-54. doi: 10.1038/sj.bjp.0704440.
• [29] Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene. FEBS Lett. 2009 May 19;583(10):1599-604. doi: 10.1016/j.febslet.2009.04.024. Epub 2009 Apr 19.