Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5Q7ODW)

• DOT Name: Leptin (LEP)
• Synonyms: Obese protein; Obesity factor
• Gene Name: LEP
• Related Disease: Obesity due to congenital leptin deficiency
• UniProt ID: LEP_HUMAN
• PDB ID: 1AX8; 7Z3Q; 8AVE; 8AVF; 8AVO
• Pfam ID: PF02024
• Sequence:
  MHWGTLCGFLWLWPYLFYVQAVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGL
  DFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLP
  WASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC
• Function: Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways. In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity. In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides. In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption. Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways. May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression. Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells. Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38. In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses. Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation.
• Tissue Specificity: Adipose tissue is the main source of leptin. It is also produced by other peripheral tissues such as the skeletal muscle . Expressed by intercalated and striated tracts of submandibular and parotid salivary gland intralobular ducts . Detected by fundic epithelium of the gastric mucosa . Secreted into blood and gastric juice .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Neuroactive ligand-receptor interaction (hsa04080)
  AMPK sig.ling pathway (hsa04152)
  JAK-STAT sig.ling pathway (hsa04630)
  Adipocytokine sig.ling pathway (hsa04920)
  Non-alcoholic fatty liver disease (hsa04932)
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)
  Synthesis, secretion, and deacylation of Ghrelin (R-HSA-422085)
  Signaling by Leptin (R-HSA-2586552)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obesity due to congenital leptin deficiency	DISIWOVJ	Strong	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Leptin (LEP) decreases the abundance of Selenium.	[39]
Manganese	DMKT129	Investigative	Leptin (LEP) decreases the abundance of Manganese.	[39]
[3H]cAMP	DMZRQU7	Investigative	Leptin (LEP) increases the abundance of [3H]cAMP.	[29]
Hydroxyestradiol	DMJXQME	Investigative	Leptin (LEP) increases the abundance of Hydroxyestradiol.	[42]
Anandamide	DMCKH3P	Investigative	Leptin (LEP) decreases the abundance of Anandamide.	[43]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Leptin (LEP) affects the response to substance of Clozapine.	[40]
Imatinib	DM7RJXL	Approved	Leptin (LEP) increases the Chronic myeloid leukaemia ADR of Imatinib.	[41]
Epinephrine	DM3KJBC	Approved	Leptin (LEP) increases the Drug ineffective ADR of Epinephrine.	[41]

42 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Leptin (LEP).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Leptin (LEP).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Leptin (LEP).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Leptin (LEP).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Leptin (LEP).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Leptin (LEP).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Leptin (LEP).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Leptin (LEP).	[9]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Leptin (LEP).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Leptin (LEP).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Leptin (LEP).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Leptin (LEP).	[13]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Leptin (LEP).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Leptin (LEP).	[15]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of Leptin (LEP).	[15]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the expression of Leptin (LEP).	[17]
Olanzapine	DMPFN6Y	Approved	Olanzapine increases the expression of Leptin (LEP).	[18]
Melatonin	DMKWFBT	Approved	Melatonin decreases the expression of Leptin (LEP).	[19]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Eicosapentaenoic acid/docosa-hexaenoic acid decreases the expression of Leptin (LEP).	[20]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Leptin (LEP).	[21]
Nelfinavir mesylate	DMFX6G8	Approved	Nelfinavir mesylate decreases the expression of Leptin (LEP).	[15]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 increases the expression of Leptin (LEP).	[22]
Efavirenz	DMC0GSJ	Approved	Efavirenz decreases the expression of Leptin (LEP).	[21]
Ketamine	DMT5HA4	Approved	Ketamine decreases the expression of Leptin (LEP).	[23]
Amlodipine	DMBDAZV	Approved	Amlodipine decreases the expression of Leptin (LEP).	[24]
Stavudine	DM6DEK9	Approved	Stavudine decreases the expression of Leptin (LEP).	[15]
Indinavir	DM0T3YH	Approved	Indinavir decreases the expression of Leptin (LEP).	[15]
Methadone	DMTW6IU	Approved	Methadone increases the expression of Leptin (LEP).	[25]
Lopinavir	DMITQS0	Approved	Lopinavir decreases the expression of Leptin (LEP).	[15]
Candesartan	DMRK8OT	Approved	Candesartan decreases the expression of Leptin (LEP).	[26]
Ramipril	DM2R68E	Approved	Ramipril decreases the expression of Leptin (LEP).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Leptin (LEP).	[27]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Leptin (LEP).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Leptin (LEP).	[31]
4-Hydroxybenzoicacid	DM3WQNY	Patented	4-Hydroxybenzoicacid decreases the expression of Leptin (LEP).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leptin (LEP).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leptin (LEP).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Leptin (LEP).	[35]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Leptin (LEP).	[32]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Leptin (LEP).	[36]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Leptin (LEP).	[37]
Icosapentum	DMF1CM7	Investigative	Icosapentum decreases the expression of Leptin (LEP).	[20]

11 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Progesterone decreases the secretion of Leptin (LEP).	[10]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the secretion of Leptin (LEP).	[16]
Dobutamine	DMD1B8Z	Approved	Dobutamine decreases the secretion of Leptin (LEP).	[16]
Fenoterol	DMIP3ZV	Approved	Fenoterol decreases the secretion of Leptin (LEP).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the response to substance of Leptin (LEP).	[29]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the response to substance of Leptin (LEP).	[33]
D-glucose	DMMG2TO	Investigative	D-glucose increases the response to substance of Leptin (LEP).	[29]
PD98059	DMZC90M	Investigative	PD98059 decreases the response to substance of Leptin (LEP).	[33]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) increases the secretion of Leptin (LEP).	[38]
H-89	DM4RVGO	Investigative	H-89 decreases the response to substance of Leptin (LEP).	[29]
Thenoyltrifluoroacetone	DM54OKX	Investigative	Thenoyltrifluoroacetone decreases the response to substance of Leptin (LEP).	[29]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Leptin (LEP).	[30]

References

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