Details of the Drug Combination

General Information of Drug Combination (ID: DCFM71H)

• Drug Combination Name: Orlistat + Velneperit
• Indication: Obesity; Status: Phase 1 [1]
• Component Drugs:
  Orlistat (DMRJSP8): Small molecular drug
  Velneperit (DMROSHN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Orlistat

Disease Entry	ICD 11	Status	REF
Obesity	5B81	Approved	[2]

Orlistat Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cannabinoid receptor 1 (CB1)	TT6OEDT	CNR1_HUMAN	Inhibitor	[4]
Pancreatic triacylglycerol lipase (PNLIP)	TTXMY0J	LIPP_HUMAN	Modulator	[5]

Orlistat Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Phosphatidylserine lipase ABHD16A (ABHD16A)	OTDS9K1Z	ABHGA_HUMAN	Decreases Activity	[6]
Lysophosphatidylserine lipase ABHD12 (ABHD12)	OTDP4F02	ABD12_HUMAN	Decreases Activity	[6]
Acyl-coenzyme A thioesterase 8 (ACOT8)	OTHY684G	ACOT8_HUMAN	Decreases Expression	[7]
ER lumen protein-retaining receptor 3 (KDELR3)	OTW8C1V0	ERD23_HUMAN	Increases Expression	[8]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[9]
Protein transport protein Sec24D (SEC24D)	OTXR3KC9	SC24D_HUMAN	Increases Expression	[8]
Pro-glucagon (GCG)	OTXU08VF	GLUC_HUMAN	Decreases Expression	[10]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Increases Expression	[11]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[12]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[13]
Eukaryotic translation initiation factor 4E (EIF4E)	OTDAWNLA	IF4E_HUMAN	Increases Phosphorylation	[8]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[12]
Peptide YY (PYY)	OTXX6AF5	PYY_HUMAN	Decreases Secretion	[14]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[15]
Carnitine O-palmitoyltransferase 2, mitochondrial (CPT2)	OTIN6G20	CPT2_HUMAN	Decreases Expression	[7]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Decreases Expression	[16]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[15]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[7]
ETS translocation variant 4 (ETV4)	OT8C98UZ	ETV4_HUMAN	Increases Expression	[12]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[13]
Carnitine O-palmitoyltransferase 1, liver isoform (CPT1A)	OTI862QH	CPT1A_HUMAN	Decreases Expression	[7]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[8]
Pancreatic lipase-related protein 2 (PNLIPRP2)	OTJG6BA7	LIPR2_HUMAN	Decreases Activity	[17]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[18]
Hemoglobin subunit alpha (HBA1)	OTW2BQF4	HBA_HUMAN	Decreases Expression	[19]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Decreases Expression	[16]
Keratin, type II cuticular Hb1 (KRT81)	OTMKIK2S	KRT81_HUMAN	Increases Expression	[8]
Probable glutathione peroxidase 8 (GPX8)	OTTH80PN	GPX8_HUMAN	Increases Expression	[8]
Eukaryotic translation initiation factor 2A (EIF2A)	OTWXELQP	EIF2A_HUMAN	Increases Phosphorylation	[20]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[8]

Indication(s) of Velneperit

Disease Entry	ICD 11	Status	REF
Obesity	5B81	Discontinued in Phase 2	[3]

Velneperit Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Neuropeptide Y receptor type 5 (NPY5R)	TTY6EWA	NPY5R_HUMAN	Antagonist	[21]

References

• [1] ClinicalTrials.gov (NCT01126970) Double-Blind, Multi-Center, Randomized Study to Assess the Efficacy and Safety of Velneperit (S-2367) and Orlistat Administered Individually or Combined With a Reduced Calorie Diet (RCD) in Obese Subjects
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] New and emerging drug molecules against obesity. J Cardiovasc Pharmacol Ther. 2014 Jan;19(1):65-76.
• [4] Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism. J Med Chem. 2008 Nov 13;51(21):6970-9.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41.
• [7] Orlistat Displays Antitumor Activity and Enhances the Efficacy of Paclitaxel in Human Hepatoma Hep3B Cells. Chem Res Toxicol. 2019 Feb 18;32(2):255-264. doi: 10.1021/acs.chemrestox.8b00269. Epub 2019 Jan 22.
• [8] Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. J Biol Chem. 2008 Nov 14;283(46):31378-84. doi: 10.1074/jbc.M803384200. Epub 2008 Sep 16.
• [9] Investigation of Orlistat effects on PXR activation and CYP3A4 expression in primary human hepatocytes and human intestinal LS174T cells. Eur J Pharm Sci. 2010 Oct 9;41(2):276-80. doi: 10.1016/j.ejps.2010.06.019. Epub 2010 Jul 3.
• [10] Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2003 Aug;88(8):3829-34. doi: 10.1210/jc.2003-030199.
• [11] [Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects]. Pol Arch Med Wewn. 2004 Dec;112(6):1415-23.
• [12] Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene. Ann Oncol. 2005 Aug;16(8):1253-67. doi: 10.1093/annonc/mdi239. Epub 2005 May 3.
• [13] A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2. J Biol Chem. 2004 Jul 16;279(29):30540-5. doi: 10.1074/jbc.M405061200. Epub 2004 May 11.
• [14] Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations. J Clin Endocrinol Metab. 2008 Oct;93(10):3995-8. doi: 10.1210/jc.2008-0924. Epub 2008 Jul 22.
• [15] Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells. Cancer Res. 2007 Feb 1;67(3):1262-9. doi: 10.1158/0008-5472.CAN-06-1794.
• [16] Diosgenin and 4-Hydroxyisoleucine from Fenugreek Are Regulators of Genes Involved in Lipid Metabolism in The Human Colorectal Cancer Cell Line SW480. Cell J. 2021 Jan;22(4):514-522. doi: 10.22074/cellj.2021.6751. Epub 2020 Apr 22.
• [17] Further biochemical characterization of human pancreatic lipase-related protein 2 expressed in yeast cells. J Lipid Res. 2007 Jul;48(7):1539-49. doi: 10.1194/jlr.M600486-JLR200. Epub 2007 Mar 30.
• [18] Orlistat delays hepatocarcinogenesis in mice with hepatic co-activation of AKT and c-Met. Toxicol Appl Pharmacol. 2020 Apr 1;392:114918. doi: 10.1016/j.taap.2020.114918. Epub 2020 Feb 8.
• [19] Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss. Diabetes Obes Metab. 2009 Apr;11(4):361-71. doi: 10.1111/j.1463-1326.2008.00970.x. Epub 2009 Jan 22.
• [20] Click-based synthesis and proteomic profiling of lipstatin analogues. Chem Commun (Camb). 2010 Nov 28;46(44):8335-7. doi: 10.1039/c0cc01276a. Epub 2010 Jun 24.
• [21] Clinical pipeline report, company report or official report of Shionogi (2011).