Modern drug discovery for inflammatory bowel disease: The role of computational methods

Figure 1 A schematic description of the Janus kinase/STAT pathway. 1: Cytokine and cytokine receptor before interaction; 2: Ligand-reception interaction brings about conformational change that recruits the second cytokine receptor to dimerize with the first cytokine receptor; 3: The activated dimeric receptor recruits Janus kinase (JAK); 4: Thereby causing JAK to phosphorylate itself and the cytoplasmic tail of the cytokine receptor on the tyrosine residue; 5: Activated JAK phosphorylates monomeric STAT transcription factor, hence causing it to disengage from its endogenous inhibitor and dimerize; 6: The activated dimeric signal transducer and activator of transcription translocates to the nucleus; 7: Where it binds to a promoter; 8: That causes the gene expression of some inflammatory markers. JAK: Janus kinase; STAT: Signal transducer and activator of transcription.

Figure 2 Putative representations. 1: Janus kinase (JAK) 1, 2 or 3, and tyrosine kinase 2 (TYK2) with their respective catalytic/ATP-binding/Janus homology (JH) 1 site, regulatory/allosteric/JH2 site and autoinhibition loop; 2: List of anti-JAK drug family differentiated with green, pink and blue shapes; 3: Different modes of action of the drugs differentiated with the colors of the shape: (A) Drugs in group A (e.g., tofacitinib, baricitinib, ruxolitinib, upadacitinib and filgotinib) block the ATP-binding site of either/both JAK 1 or 2, while the inhibition loop is disengaged; (B) Drugs in group B (e.g., deucravacitinib) bind to the allosteric site of TYK2, thereby stabilizing the autoinhibition loop from disengaging from the catalytic domain; (C) Drugs in group C (e.g., brepocitinib and ropsacitinib) are dual inhibitors and have a similar mode of action as “A” by binding to the catalytic site of their targets but blocking the catalytic site of both JAK 1 and TYK2 or JAK2 and TYK2, respectively. JAK: Janus kinase; TYK: Tyrosine kinase; JH: Janus homology.

Figure 3 Overview of the drug discovery and development process. IND: Investigated new drug application; NDA: New drug application; UMN: Unmet medical needs.