Details of the Drug Combination

General Information of Drug Combination (ID: DCFM71H)

Drug Combination Name
Orlistat Velneperit
Indication
Disease Entry Status REF
Obesity Phase 1 [1]
Component Drugs Orlistat   DMRJSP8 Velneperit   DMROSHN
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
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]
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Orlistat Interacts with 57 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Serum paraoxonase/arylesterase 1 (PON1) OTD0Z2XO PON1_HUMAN Increases Activity [6]
Phosphatidylserine lipase ABHD16A (ABHD16A) OTDS9K1Z ABHGA_HUMAN Decreases Activity [7]
Lysophosphatidylserine lipase ABHD12 (ABHD12) OTDP4F02 ABD12_HUMAN Decreases Activity [7]
Acyl-coenzyme A thioesterase 8 (ACOT8) OTHY684G ACOT8_HUMAN Decreases Expression [8]
ER lumen protein-retaining receptor 3 (KDELR3) OTW8C1V0 ERD23_HUMAN Increases Expression [9]
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Increases Activity [10]
Protein transport protein Sec24D (SEC24D) OTXR3KC9 SC24D_HUMAN Increases Expression [9]
Pro-glucagon (GCG) OTXU08VF GLUC_HUMAN Decreases Expression [11]
Pro-neuropeptide Y (NPY) OT4ICV3P NPY_HUMAN Increases Expression [12]
Insulin (INS) OTZ85PDU INS_HUMAN Decreases Expression [13]
Catalase (CAT) OTHEBX9R CATA_HUMAN Decreases Expression [8]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Decreases Expression [14]
Cholecystokinin (CCK) OT1GCG0L CCKN_HUMAN Decreases Secretion [15]
Retinoblastoma-associated protein (RB1) OTQJUJMZ RB_HUMAN Decreases Phosphorylation [16]
Cyclin-dependent kinase 1 (CDK1) OTW1SC2N CDK1_HUMAN Decreases Expression [8]
Eukaryotic translation initiation factor 4E (EIF4E) OTDAWNLA IF4E_HUMAN Increases Phosphorylation [9]
Lipoprotein lipase (LPL) OTTW0267 LIPL_HUMAN Decreases Activity [17]
Gastric triacylglycerol lipase (LIPF) OTNMCWTI LIPF_HUMAN Decreases Activity [18]
Fatty acid-binding protein, liver (FABP1) OTR34ETM FABPL_HUMAN Decreases Expression [8]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [10]
Gastric inhibitory polypeptide (GIP) OTUFSTG9 GIP_HUMAN Decreases Expression [11]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [14]
Peptide YY (PYY) OTXX6AF5 PYY_HUMAN Decreases Secretion [15]
Endoplasmic reticulum chaperone BiP (HSPA5) OTFUIRAO BIP_HUMAN Increases Expression [19]
Cyclin-dependent kinase 4 (CDK4) OT7EP05T CDK4_HUMAN Decreases Expression [8]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4) OTRFV19J ATF4_HUMAN Increases Expression [19]
Cyclin-A2 (CCNA2) OTPHHYZJ CCNA2_HUMAN Decreases Expression [8]
Acetylcholinesterase (ACHE) OT2H8HG6 ACES_HUMAN Decreases Activity [20]
Carnitine O-palmitoyltransferase 2, mitochondrial (CPT2) OTIN6G20 CPT2_HUMAN Decreases Expression [8]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Increases Expression [8]
G1/S-specific cyclin-E1 (CCNE1) OTLD7UID CCNE1_HUMAN Increases Expression [8]
Cyclin-dependent kinase 2 (CDK2) OTB5DYYZ CDK2_HUMAN Decreases Expression [8]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Decreases Expression [21]
DNA damage-inducible transcript 3 protein (DDIT3) OTI8YKKE DDIT3_HUMAN Increases Expression [19]
Vascular endothelial growth factor receptor 2 (KDR) OT15797V VGFR2_HUMAN Decreases Expression [22]
Sterol regulatory element-binding protein 1 (SREBF1) OTWBRPAI SRBP1_HUMAN Decreases Expression [23]
Peroxisome proliferator-activated receptor gamma (PPARG) OTHMARHO PPARG_HUMAN Increases Expression [21]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [8]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [24]
ETS translocation variant 4 (ETV4) OT8C98UZ ETV4_HUMAN Increases Expression [14]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [16]
Fatty acid synthase (FASN) OTFII9KG FAS_HUMAN Decreases Activity [25]
Carnitine O-palmitoyltransferase 1, liver isoform (CPT1A) OTI862QH CPT1A_HUMAN Decreases Expression [8]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10) OT4PXBTA TNF10_HUMAN Increases Response To Substance [9]
Palmitoyl-protein thioesterase 1 (PPT1) OTM3S4DE PPT1_HUMAN Decreases Expression [8]
Pancreatic lipase-related protein 2 (PNLIPRP2) OTJG6BA7 LIPR2_HUMAN Decreases Activity [26]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Expression [23]
Hemoglobin subunit alpha (HBA1) OTW2BQF4 HBA_HUMAN Decreases Expression [27]
Acetyl-CoA carboxylase 1 (ACACA) OT5CQPZY ACACA_HUMAN Decreases Expression [21]
Platelet-activating factor acetylhydrolase (PLA2G7) OT6H6AMO PAFA_HUMAN Decreases Activity [28]
S-phase kinase-associated protein 2 (SKP2) OTD5B41X SKP2_HUMAN Decreases Expression [16]
Keratin, type II cuticular Hb1 (KRT81) OTMKIK2S KRT81_HUMAN Increases Expression [9]
Probable glutathione peroxidase 8 (GPX8) OTTH80PN GPX8_HUMAN Increases Expression [9]
Carboxypeptidase B2 (CPB2) OTPIL8IE CBPB2_HUMAN Decreases Expression [29]
Eukaryotic translation initiation factor 2A (EIF2A) OTWXELQP EIF2A_HUMAN Increases Phosphorylation [30]
DNA damage-inducible transcript 4 protein (DDIT4) OTHY8SY4 DDIT4_HUMAN Increases Expression [9]
Diacylglycerol lipase-alpha (DAGLA) OT8GVKGM DGLA_HUMAN Decreases Activity [31]
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⏷ Show the Full List of 57 DOT(s)
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 [32]
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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 Changes in lipid profile and paraoxonase activity in obese patients as a result of orlistat treatment. Orv Hetil. 2001 Dec 16;142(50):2779-83.
7 Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41.
8 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.
9 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.
10 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.
11 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.
12 [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.
13 Effect of orlistat-assisted weight loss in decreasing coronary heart disease risk in patients with syndrome X. Am J Cardiol. 2001 Apr 1;87(7):827-31. doi: 10.1016/s0002-9149(00)01521-6.
14 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.
15 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.
16 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.
17 Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. J Biol Chem. 2005 Sep 2;280(35):31076-84. doi: 10.1074/jbc.M412189200. Epub 2005 Jul 1.
18 Inhibition of gastrointestinal lipolysis by Orlistat during digestion of test meals in healthy volunteers. Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G16-28. doi: 10.1152/ajpgi.2001.281.1.G16.
19 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.
20 Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.
21 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.
22 Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J. 2006 Oct;20(12):2027-35. doi: 10.1096/fj.05-5404com.
23 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.
24 Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed Pharmacother. 2011 Jul;65(4):286-92. doi: 10.1016/j.biopha.2011.02.016. Epub 2011 Jun 12.
25 Synthesis of novel beta-lactone inhibitors of fatty acid synthase. J Med Chem. 2008 Sep 11;51(17):5285-96. doi: 10.1021/jm800321h. Epub 2008 Aug 19.
26 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.
27 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.
28 The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. 2007 Aug;193(2):428-37. doi: 10.1016/j.atherosclerosis.2006.07.010. Epub 2006 Sep 5.
29 Decrements in the thrombin activatable fibrinolysis inhibitor (TAFI) levels in association with orlistat treatment in obesity. Clin Appl Thromb Hemost. 2006 Jul;12(3):364-8. doi: 10.1177/1076029606291403.
30 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.
31 Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim Biophys Acta. 2006 Feb;1761(2):205-12. doi: 10.1016/j.bbalip.2005.12.009. Epub 2006 Jan 23.
32 Clinical pipeline report, company report or official report of Shionogi (2011).