Details of the Drug Combination

General Information of Drug Combination (ID: DC4LPT0)

• Drug Combination Name: Sertraline + 1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Sertraline (DM0FB1J): Small molecular drug
  1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole (DMQEJVU): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 27.65
  Bliss Independence Score: 27.65
  Loewe Additivity Score: 41.91
  LHighest Single Agent (HSA) Score: 41.92

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sertraline

Disease Entry	ICD 11	Status	REF
Coronary heart disease	BA80.Z	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Epilepsy	8A60-8A68	Approved	[2]
Obsessive compulsive disorder	6B20	Approved	[2]
Panic disorder	6B01	Approved	[2]
Post-traumatic stress disorder	6B40	Approved	[2]

Sertraline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Inhibitor	[9]

Sertraline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Sertraline Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[16]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[16]

Sertraline Interacts with 88 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[17]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[18]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Methylation	[19]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Activity	[20]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Increases Expression	[5]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[5]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[5]
Serine protease hepsin (HPN)	OT7QNA61	HEPS_HUMAN	Increases Expression	[5]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Increases Expression	[5]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[5]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[5]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Increases Expression	[5]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[5]
Transgelin (TAGLN)	OTAEZ0KP	TAGL_HUMAN	Decreases Expression	[5]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[5]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[5]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[5]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[5]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[5]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[21]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Expression	[21]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[22]
Mitogen-activated protein kinase kinase kinase 13 (MAP3K13)	OTS93BTX	M3K13_HUMAN	Increases Expression	[6]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B)	OTL9I7LO	GA45B_HUMAN	Increases Expression	[6]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[6]
Protein phosphatase 1 regulatory subunit 15A (PPP1R15A)	OTYG179K	PR15A_HUMAN	Increases Expression	[6]
Dual specificity protein phosphatase 14 (DUSP14)	OTGODFCR	DUS14_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4)	OTBMJUOC	M4K4_HUMAN	Decreases Expression	[6]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Expression	[6]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[6]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[6]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[23]
Alpha-crystallin A chain (CRYAA)	OTSN7JUR	CRYAA_HUMAN	Increases Expression	[6]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[24]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[25]
Platelet factor 4 (PF4)	OTEMJU68	PLF4_HUMAN	Decreases Expression	[7]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[6]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[6]
Transcription factor AP-2-alpha (TFAP2A)	OTMYT3NK	AP2A_HUMAN	Increases Expression	[26]
Monocyte differentiation antigen CD14 (CD14)	OT83GJ47	CD14_HUMAN	Decreases Expression	[6]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[6]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[23]
Heat shock cognate 71 kDa protein (HSPA8)	OTJI2RCI	HSP7C_HUMAN	Decreases Expression	[6]
Cyclic AMP-dependent transcription factor ATF-2 (ATF2)	OTNIZPEA	ATF2_HUMAN	Increases Expression	[6]
P-selectin (SELP)	OTWR90PK	LYAM3_HUMAN	Decreases Expression	[25]
Platelet endothelial cell adhesion molecule (PECAM1)	OTXOM4D9	PECA1_HUMAN	Decreases Expression	[7]
E-selectin (SELE)	OT33RZWY	LYAM2_HUMAN	Decreases Expression	[25]
Stathmin (STMN1)	OTDJ4RV0	STMN1_HUMAN	Decreases Expression	[6]
Heat shock 70 kDa protein 6 (HSPA6)	OTH4S7WB	HSP76_HUMAN	Increases Expression	[6]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[6]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[6]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[6]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[8]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[23]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[23]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Increases Expression	[6]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase kinase kinase 8 (MAP3K8)	OTOZTA1F	M3K8_HUMAN	Increases Expression	[6]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[6]
Translocon-associated protein subunit beta (SSR2)	OTQJSL7M	SSRB_HUMAN	Increases Expression	[6]
Caspase-4 (CASP4)	OTVQTV1L	CASP4_HUMAN	Increases Cleavage	[6]
Ribosomal protein S6 kinase alpha-3 (RPS6KA3)	OTYJNNMD	KS6A3_HUMAN	Decreases Expression	[6]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[6]
Protein transport protein Sec61 subunit gamma (SEC61G)	OT7MJRXY	SC61G_HUMAN	Decreases Expression	[6]
E3 ubiquitin-protein ligase RBX1 (RBX1)	OTYA1UIO	RBX1_HUMAN	Decreases Expression	[6]
S-phase kinase-associated protein 1 (SKP1)	OT5BPAZ4	SKP1_HUMAN	Decreases Expression	[6]
Nuclear factor NF-kappa-B p100 subunit (NFKB2)	OTS231V7	NFKB2_HUMAN	Increases Expression	[6]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Increases Expression	[6]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[23]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[27]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[8]
Dual specificity protein phosphatase 8 (DUSP8)	OTPLMPG9	DUS8_HUMAN	Increases Expression	[6]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[8]
Cullin-1 (CUL1)	OTXPE1UZ	CUL1_HUMAN	Decreases Expression	[6]
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein (HERPUD1)	OT9EROL6	HERP1_HUMAN	Increases Expression	[6]
Serine/threonine-protein kinase STK11 (STK11)	OT1YZSP3	STK11_HUMAN	Increases Phosphorylation	[8]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[6]
E3 ubiquitin-protein ligase synoviolin (SYVN1)	OTZ4ZJP5	SYVN1_HUMAN	Increases Expression	[6]
Dual specificity protein phosphatase 16 (DUSP16)	OTK7S078	DUS16_HUMAN	Increases Expression	[6]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[8]
DnaJ homolog subfamily C member 5 (DNAJC5)	OTCZDXAL	DNJC5_HUMAN	Increases Expression	[28]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[6]
Serine/threonine-protein kinase TAO2 (TAOK2)	OTNUMOZ1	TAOK2_HUMAN	Increases Expression	[6]
C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3)	OT0X8ACY	JIP3_HUMAN	Increases Expression	[6]
Dual specificity protein phosphatase 10 (DUSP10)	OTNG467B	DUS10_HUMAN	Increases Expression	[6]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Response To Substance	[29]

Indication(s) of 1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole

Disease Entry	ICD 11	Status	REF
Conjunctival fibrosis	9A61.3	Investigative	[4]

1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcium-activated potassium channel (KCN)	TTMNI76	NOUNIPROTAC	Inhibitor	[30]
Calcium-activated potassium channel KCa3.1 (KCNN4)	TT7M9I6	KCNN4_HUMAN	Blocker (channel blocker)	[31]

1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Expression	[32]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Increases Expression	[32]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Sertraline FDA Label
• [3] 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: 4798).
• [4] Blockade of KCa3.1: A novel target to treat TGF-1 induced conjunctival fibrosis.Exp Eye Res. 2018 Feb;167:140-144.
• [5] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [6] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [7] Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. Am J Psychiatry. 2005 Jun;162(6):1165-70. doi: 10.1176/appi.ajp.162.6.1165.
• [8] Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein. Autophagy. 2021 Oct;17(10):2783-2799. doi: 10.1080/15548627.2020.1841953. Epub 2020 Nov 9.
• [9] Psychopharmacological treatment of dermatological patients--when simply talking does not help. J Dtsch Dermatol Ges. 2007 Dec;5(12):1101-6.
• [10] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [11] New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther Clin Risk Manag. 2014 Jun 13;10:423-36.
• [12] The selective serotonin reuptake inhibitor sertraline: its profile and use in psychiatric disorders. CNS Drug Rev. 2001 Spring;7(1):1-24.
• [13] Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie. 2004 Jan-Feb;59(1):5-12.
• [14] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA166181117)
• [15] Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005 Feb;33(2):262-70.
• [16] Influence of CYP2B6 and CYP2C19 polymorphisms on sertraline metabolism in major depression patients. Int J Clin Pharm. 2016 Apr;38(2):388-94.
• [17] Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class. Toxicol Lett. 2016 Jan 22;241:82-94.
• [18] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [19] Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther. 2001 Jul;70(1):42-7.
• [20] Michaelis-Menten kinetic analysis of drugs of abuse to estimate their affinity to human P-glycoprotein. Toxicol Lett. 2013 Feb 27;217(2):137-42. doi: 10.1016/j.toxlet.2012.12.012. Epub 2012 Dec 27.
• [21] Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression. Eur Neuropsychopharmacol. 2007 Dec;17(12):774-80.
• [22] Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay. Toxicol In Vitro. 2015 Oct;29(7):1729-35.
• [23] Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway. Toxicol Sci. 2014 Feb;137(2):404-15. doi: 10.1093/toxsci/kft254. Epub 2013 Nov 5.
• [24] Exploring binding properties of sertraline with human serum albumin: Combination of spectroscopic and molecular modeling studies. Chem Biol Interact. 2015 Dec 5;242:235-46. doi: 10.1016/j.cbi.2015.10.006. Epub 2015 Oct 22.
• [25] Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation. 2003 Aug 26;108(8):939-44. doi: 10.1161/01.CIR.0000085163.21752.0A. Epub 2003 Aug 11.
• [26] Impact of selective serotonin reuptake inhibitors on neural crest stem cell formation. Toxicol Lett. 2017 Nov 5;281:20-25. doi: 10.1016/j.toxlet.2017.08.012. Epub 2017 Aug 24.
• [27] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [28] Induction of cysteine string protein after chronic antidepressant treatment in rat frontal cortex. Neurosci Lett. 2001 Apr 6;301(3):183-6. doi: 10.1016/s0304-3940(01)01638-x.
• [29] The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berl). 2004 Aug;174(4):525-9. doi: 10.1007/s00213-003-1562-3. Epub 2003 Sep 4.
• [30] Inhibitors of potassium channels KV1.3 and IK-1 as immunosuppressants. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2299-304.
• [31] Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. Circulation. 2003 Sep 2;108(9):1119-25.
• [32] The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors. Br J Pharmacol. 2010 Feb 1;159(3):650-8. doi: 10.1111/j.1476-5381.2009.00557.x. Epub 2009 Dec 24.