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 1 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]

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	[8]

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	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]
Vesicular acetylcholine transporter (SLC18A3)	DT3T2K0	VACHT_HUMAN	Substrate	[11]
Choline transporter-like protein 4 (SLC44A4)	DT8KXR9	CTL4_HUMAN	Substrate	[12]

Acetylcholine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Acetylcholinesterase (ACHE)	DEQ2BAJ	ACES_HUMAN	Metabolism	[13]

Acetylcholine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Secreted Ly-6/uPAR-related protein 1 (SLURP1)	OT89YD2E	SLUR1_HUMAN	Increases Abundance	[14]
Interleukin-5 receptor subunit alpha (IL5RA)	OTMSLUG9	IL5RA_HUMAN	Increases Response To Substance	[15]

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.
• [7] Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. J Urol. 2003 Mar;169(3):1048-51. doi: 10.1097/01.ju.0000058369.72348.ba.
• [8] Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol Pharmacol. 2004 Jan;65(1):257-66.
• [9] Organic cation transporters: physiology, toxicology and special focus on ethidium as a novel substrate. Curr Drug Metab. 2009 Jul;10(6):617-31.
• [10] Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir Res. 2006 Apr 12;7:65.
• [11] SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013 Apr-Jun;34(2-3):360-72.
• [12] Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis. J Neurochem. 2013 Aug;126(4):451-61.
• [13] How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [14] 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.
• [15] 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.