Details of the Drug Combination

General Information of Drug Combination (ID: DCCW82P)

• Drug Combination Name: Cycloserine + Fludrocortisone
• Indication: Major Depression; Status: Phase 1 [1]
• Component Drugs:
  Cycloserine (DMT1I52): Small molecular drug
  Fludrocortisone (DMUDIR8): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cycloserine

Disease Entry	ICD 11	Status	REF
Bacterial infection	1A00-1C4Z	Approved	[2]
Pulmonary tuberculosis	1B10.Z	Approved	[3]
Tuberculosis	1B10-1B14	Approved	[4]
Obsessive compulsive disorder	6B20	Phase 2	[2]

Cycloserine Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mycobacterium D-alanine-D-alanine ligase A (MycB ddl)	TTCS3P1	DDL_MYCTU	Inhibitor	[7]
Mycobacterium Biosynthetic alanine racemase (MycB alr)	TT6TMZU	ALR_MYCSM	Inhibitor	[8]
Glutamate receptor ionotropic NMDA 1 (NMDAR1)	TTLD29N	NMDZ1_HUMAN	Inhibitor	[8]
N-methyl-D-aspartate receptor (NMDAR)	TT9IK2Z	NOUNIPROTAC	Agonist	[9]

Cycloserine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Proton-coupled amino acid transporter 1 (SLC36A1)	DT48WEM	S36A1_HUMAN	Substrate	[10]
Proton-coupled amino acid transporter 2 (SLC36A2)	DTAOPTV	S36A2_HUMAN	Substrate	[11]

Indication(s) of Fludrocortisone

Disease Entry	ICD 11	Status	REF
Addison disease	5A74.0	Approved	[5]
Cerebral salt-wasting syndrome	5C72	Approved	[6]
Congenital adrenal hyperplasia	5A71.01	Approved	[5]

Fludrocortisone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Androgen receptor (AR)	TTS64P2	ANDR_HUMAN	Inhibitor	[13]
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Agonist	[14]

Fludrocortisone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]

Fludrocortisone Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Decreases Expression	[16]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[16]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[16]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[16]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[17]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[16]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[16]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[12]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[12]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[12]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[16]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[16]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[16]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[16]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[16]

References

• [1] ClinicalTrials.gov (NCT03062150) Mineralocorticoid Receptor, NMDA Receptor and Cognitive Function in Depression
• [2] Has nature already identified all useful antibacterial targets Curr Opin Microbiol. 2008 Oct;11(5):387-92.
• [3] Cycloserine FDA Label
• [4] Novel agents in the management of Mycobacterium tuberculosis disease. Curr Med Chem. 2007;14(18):2000-8.
• [5] Fludrocortisone FDA Label
• [6] 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: 2873).
• [7] Self-protection mechanism in D-cycloserine-producing Streptomyces lavendulae. Gene cloning, characterization, and kinetics of its alanine racemase ... J Biol Chem. 2004 Oct 29;279(44):46143-52.
• [8] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [9] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [10] Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1). J Cell Physiol. 2005 Aug;204(2):604-13.
• [11] Substrate specificity and functional characterisation of the H+/amino acid transporter rat PAT2 (Slc36a2). Br J Pharmacol. 2005 Jan;144(1):28-41.
• [12] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [13] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [14] Mineralocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in aged humans. J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):B900-5.
• [15] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [16] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [17] A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer. Endocrinology. 2002 May;143(5):1889-900. doi: 10.1210/endo.143.5.8778.