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©The Author(s) 2023.
World J Gastroenterol. Jan 14, 2023; 29(2): 310-331
Published online Jan 14, 2023. doi: 10.3748/wjg.v29.i2.310
Published online Jan 14, 2023. doi: 10.3748/wjg.v29.i2.310
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 |
Table 2 Bioinformatics resources for the identification of drug targets
| Tool/Database | Description |
| Open Targets Platform | To facilitate systematic target identification and prioritization for drug discovery based on underlying evidence, the Open Targets Platform offers users a searchable knowledgebase and user interface[123] |
| SELF-BLM | A self-training support vector machine-based bipartite local model that predicts drug-target interactions[136] |
| iDTIESBoost | A model for detecting drug-target interactions based on evolutionary and structural features[137] |
| GEO | Database that stores array- and sequence-based transcriptomics data that can be applied to functional genomics[138] |
| DASPfind | Predicts drug-target protein interactions that stem from shared structural features[139] |
| NetCBP | Network methods for predicting drug-target interactions. Furthermore, it suggests new drugs even when no data on their interactions with their targets are available[140] |
| DbMDR | Offers a database of multidrug resistance (MDR) genes and their orthologs, which could be used to develop new treatments[141] |
| TDR targets | Drug development molecular target identification and prioritization[142] |
| DrugBank | An extensive drug database with annotations covering drug targets and mechanisms of action[143] |
| PDTD | Database of potential proteins for in silico drug target identification[144] |
| DEG | Contains all known essential genes from different organisms[145] |
| TTD | Publicly accessible cross-links database that provides inclusive information about known therapeutic targets with related information, i.e. pathway information and the corresponding drugs/ligands[146] |
| KEGG | Offers information about the pathway, gene and ligands in three different databases, i.e. Pathway, Gene and Ligand[147] |
| Genecards | Officially known as Genecards: The Human Gene Database, it is an all-inclusive, authoritative compilation of annotative information about human genes[148] |
| DisGeNET | A public resource that houses a massive database of genetic variants and their links to human disease[149] |
| CTD | The Comparative Toxicogenomics Database is a vast, freely accessible database with the objective of increasing understanding of the effects of environmental exposures on human health. It includes information on chemical-gene/protein interactions, chemical-disease relationships and gene-disease links that has been curated by humans[150] |
| UniProt | The Universal Protein Resource is the world’s most comprehensive, high-quality and freely accessible database of protein sequence and functional information[151] |
Table 3 Molecular docking programs most frequently employed in drug discovery
| Program | Description | Website |
| AutoDock[152] | A docking toolkit. It is meant to foretell the binding mode of small molecules to a receptor with a known 3D structure, such as a substrate or a drug candidate. There have been multiple engines developed, and it has undergone constant evolution and refinement over the years to incorporate new features | https://autodock.scripps.edu/ |
| AutoDock Vina[153] | One of the AutoDock Suite’s docking engines. It is a free and open-source molecular docking software. Dr. Oleg Trott of The Scripps Research Institute’s Molecular Graphics Lab (now CCSB) created and initially implemented the system. The most recent version of AutoDock Vina is v.1.2.0 | https://vina.scripps.edu/ |
| Hex[154] | Invented by Dave Ritchie and is a program for molecular superposition and protein docking. Hex can read protein and DNA structures in the Protein Data Bank format as well as small-molecule SDF files. It has been downloaded over 40000 times as of December 2015 | http://hex.loria.fr/ |
| MOE[155] | Integrated computer-aided molecular design platform for small molecule and biological therapeutics. Common platform for chemists, biologists and crystallographers. Small Molecules - Peptides – Biologics | https://www.chemcomp.com/ |
| Glide Schrodinger[156] | Provides a full range of speed vs accuracy options, ranging from the high-throughput virtual screening mode that efficiently enriches million compound libraries to the standard precision) mode that reliably docks tens to hundreds of thousands of ligands with high accuracy to the extra precision mode that eliminates false positives by sampling more extensively and using more advanced scoring, resulting in even higher enrichment | https://www.schrodinger.com/ |
- Citation: Johnson TO, Akinsanmi AO, Ejembi SA, Adeyemi OE, Oche JR, Johnson GI, Adegboyega AE. Modern drug discovery for inflammatory bowel disease: The role of computational methods. World J Gastroenterol 2023; 29(2): 310-331
- URL: https://www.wjgnet.com/1007-9327/full/v29/i2/310.htm
- DOI: https://dx.doi.org/10.3748/wjg.v29.i2.310