Table 1.

Molecular targets for inflammatory bowel disease drug discovery

Target name	Abbreviation	Description	Disease implication	Modulatory effect of drug
Integrin alpha-4	ITGA4	A member of the family of integrins. Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are fibronectin and VCAM1 receptors. Integrin alpha-4/beta-7 is also a MADCAM1 receptor. On activated endothelial cells, VLA-4 integrin induces homotypic aggregation in the majority of VLA-4-positive leukocyte cell lines. ITGA4: ITGB1 binds fractalkine (CX3CL1) and may function as its coreceptor in fractalkine signaling dependent on CX3CR1[123]	ITGA4 upregulated in irritable bowel disease (IBD)	Inhibition
Interleukin 12B	IL12B	IL12B is also known as natural killer cell stimulatory factor 2 or p40, and it associates with IL23A to form IL23, a known stimulator of the JAK/signal transducer and activator of transcription (STAT) signaling pathway and a pathway with proven importance in IBD[124]	IL12B upregulated in IBD	Inhibition
Tumor necrosis factor	TNF	A type of cytokine, which binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is secreted by macrophages and is capable of triggering cell death of most tumor cell lines, although capable of promoting cell proliferation and induce cell differentiation under certain conditions[123]	TNF upregulated in IBD	Inhibition
Janus kinase 2	JAK2	A class of kinase, a non-receptor kinase that phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor. In the cytoplasm, JAK2 plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO) or type II receptors including IFN-alpha, IFN-beta, IFN-gamma, and multiple interleukins. It stimulates cell growth, development, differentiation or histone modification[123]	JAK2 upregulated in IBD	Inhibition
Prostaglandin-endoperoxide synthase 1 and 2	PTGS1/2	Also referred to as cyclooxygenase; are the primary enzymes involved in the synthesis of prostaglandin. They act both as a dioxygenase and as peroxidase, having two isozymes PTGS1 and PTGS2. This gene encodes the PTGS2 inducible isozyme. Its involvement in prostanoid-dependent inflammation and mitogenesis can be related to their regulation by specific stimulation[123]	PTGS1/2 upregulated in IBD	Inhibition
Peroxisome proliferator activated receptor gamma	PPARγ	A nuclear receptor. It consists of a group of approximately 50 transcription factors involved in many biological processes. It controls some regulatory genes involved in lipid metabolism and insulin sensitization as well as in inflammation and cell proliferation. It is highly expressed in the colon and majorly involved in bacterial-induced inflammation, also mediating the common aminosalicylate activities in IBD[125]. It acts as a critical regulator of gut homeostasis by suppressing nuclear factor-kappa B-mediated proinflammatory responses	PPARγ downregulated in IBD, mostly ulcerative colitis	Activation
Integrin subunit beta 7	ITGB7	Integrin alpha-4/beta-7 is an adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT). The vascular endothelium of the gastrointestinal tract expresses MADCAM1, an adhesion molecule, which is the medium integrin alpha-4/beta-7 interacts with the gastrointestinal tract. VCAM1 and fibronectin found on the extracellular matrix of the cell also interacts with the integrin. Interaction with fibronectin is due to the CS-1 region[123]	ITGB7 upregulated in IBD	Inhibition
Nuclear receptor subfamily 3 group C member 1	NR3C1	This is a receptor recognized by glucocorticoids. It modulates the activities of cortisol and acts as a transcription factor that modulates the expression of its target genes[126]. It modulates inflammatory responses, cellular proliferation and differentiation in target tissues	NR3C1 downregulated in IBD	Activation
Janus kinase 3	JAK3	Non-receptor tyrosine kinase involved in signal transduction in the cytoplasm via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R, and IL21R. It also plays a vital role in STAT5 activation. IBD pathology is associated with receptor-mediated signaling through the JAK and STAT DNA-binding families of proteins[127]	JAK3 upregulated in IBD	Inhibition
Arachidonate 5-lipoxygenase	ALOX5	ALOX5, an important member of the lipoxygenase gene family, exclusively involved in IBD development[128]. Catalyzes the oxygenation of arachidonate (5Z,8Z,11Z,14Z)- eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (leukotriene A4/LTA4), the steps in the biosynthesis of leukotrienes, that mediates inflammation[123]	ALOX5 upregulated in IBD, especially ulcerative colitis	Inhibition
Tyrosine kinase 2	TYK2	A non-receptor kinase that carries out both structural and catalytic roles in numerous cytokines and interferons signaling. TYK2 plays a key role in mediating signaling and functional responses downstream of the IL-12, IL-23, and type I interferon (IFN) receptors and TYK2-mediated IL-12, IL-23 and type I IFN signaling activates STAT-dependent transcription, which promotes chronic inflammation[129]	TYK2 upregulated in IBD	Inhibition
Phosphoribosyl pyrophosphate aminotransferase	PPAT	PPAT is a key rate-limiting reaction in purine biosynthesis, transferring gamma-nitrogen from glutamine to 5-phosphoribosyl pyrophosphate (PRPP)[130]	PPAT upregulated in IBD	Inhibition
Vitamin D receptor	VDR	A nuclear, ligand-dependent transcription factor that regulates the expression of T cells and genes involved in different physiological functions when in complex with hormonally active vitamin D, 1,25(OH)2D3[131]. VDR plays a multifaceted role in the pathogenesis of IBD and is crucial in regulating autophagy, immune response, tight junctions, gut microbiome, and metabolites[132]	VDR downregulated in Crohn’s disease	Activation
Matrix metallopeptidase 1	MMP1	An interstitial collagenase, that digests the spiral structure of collagen types I, II, III and X, subjecting them to hydrolysis by gelatinase and are major players in extracellular matrix degradation[123]	MMP1 upregulated in IBD	Inhibition
Matrix metallopeptidase 7	MMP7	A metallopeptidase member necessary for neutrophil migration into the airspaces by cleaving syndecan-1, a heparin sulfate proteoglycan necessary for the establishment of a neutrophil chemokine gradient[133]. Degrades casein, gelatins I, III, IV and V, and fibronectin and is responsible for the activation of procollagenase[123]	MMP7 upregulated in IBD	Inhibition
Dihydrofolate reductase	DHFR	An enzyme that converts dihydrofolate to tetrahydrofolate in folate metabolism and involved in purine and mitochondrial thymidylate biosynthesis[123]	DHFR upregulated in Crohn’s disease	Inhibition
Matrix metallopeptidase 13	MMP13	A member of the family of collagenases. Matrix substrates of MMP13 include native collagen, gelatin and aggrecan. Lipopolysaccharide (LPS)-induced shock and dioctyl sodium sulfosuccinate (DSS)-induced colitis induce MMP13 upregulation in the gut, which results in MMP13-mediated shedding of transmembrane-bound TNF and release of bioactive, soluble TNF, thus triggering a cascade that leads to leakage of intestinal components, which increases systemic inflammation and subsequent organ damage[134]	MMP13 upregulated in IBD	Inhibition
Sphingosine-1-phosphate receptor 1	S1PR1	A type of G-protein-coupled receptor. S1P binds to the S1PR1, which triggers angiogenesis, endothelial barrier enhancement, blood vessel constriction, heart rate modulation and lymphocyte trafficking[135]	S1PR1 downregulated in IBD	Activation
ATPase H+/K+ transporting subunit alpha	ATP4A	A P-type cation-transporting ATPase. The gastric H+, K+-ATPase is a heterodimer made of high molecular, weight catalytic alpha subunit with a glycosylated beta subunit. It is a proton pump that catalyzes the hydrolysis of ATP coupled with the exchange of H (+) for K (+) ions across the plasma membrane and also responsible for gastric acid secretion due to its ability to generate proton gradient across the membrane[123]	ATP4A upregulated in IBD	Inhibition

IBD: Inflammatory Bowel Disease; ITGA4: Integrin alpha-4; IL: Interleukin; TNF: Tumor necrosis factor; JAK: Janus kinase; PTGS1/2: Prostaglandin-endoperoxide synthase 1 and 2; PPARγ: Peroxisome proliferator activated receptor gamma; ITGB7: Integrin subunit beta 7; NR3C1: Nuclear receptor subfamily 3 group C member; ALOX5: Arachidonate 5-lipoxygenase; TYK2: Tyrosine kinase 2; PPAT: Phosphoribosyl pyrophosphate aminotransferase; VDR: Vitamin D receptor; MMP: Matrix metallopeptidase; DHFR: Dihydrofolate reductase; S1PR1: Sphingosine-1-phosphate receptor 1; ATP4A: ATPase H+/K+ transporting subunit alpha; VLA-4: Very late antigen-4; VCAM 1: Vascular cell adhesion molecule 1; MADCAM1: Mucosal vascular addressin cell adhesion molecule 1; CX3CL1: C-X3-C Motif Chemokine Ligand 1; CX3CR1: C-X3-C Motif Chemokine Receptor 1; STAT: Signal transducer and activator of transcription; TNFRSF: Tumor necrosis factor receptor superfamily; GHR: Growth hormone receptor; PRLR: Prolactin receptor; LEPR: Leptin receptor, EPOR: Erythropoietin receptor; THPO: Thrombopoietin; IFN: Interferon; PTGS1&2: Prostaglandin G/H synthase 1 & 2; GALT: Gut-associated lymphoid tissue; 5-HPETE: 5-hydroperoxyeicosatetraenoate; LTA4: Leukotriene A4; prpp: Phosphoribosyl pyrophosphate.