Computational approaches to pleiotropic drug design for intestinal ischemia-reperfusion injury

Intestinal ischemia-reperfusion injury (IRI) is a life-threatening condition with mortality rates of 60–80% for which no approved pharmacotherapy exists. Its pathophysiology makes single-target pharmacological strategies fundamentally insufficient as it involves the simultaneous activation of oxidative stress, NF-κB-driven inflammation, NLRP3 inflammasome-mediated pyroptosis, as well as multiple cell death pathways, and intestinal barrier collapse. Pleiotropic drug design, in which a single therapeutic agent engages multiple disease-relevant molecular targets simultaneously, offers a mechanistically rational alternative. Also, computational pharmacology provides the analytical framework that can help to identify, characterise, and optimise such multi-target candidates at a scale and resolution that classical pharmacological approaches cannot achieve. This review examines published computational evidence on network pharmacology, molecular docking, molecular dynamics simulation, and ADMET profiling to evaluate candidate pleiotropic drugs and hub targets for intestinal IRI. The IRI pathophysiological landscape was mapped as a druggable target network. To this end, the NF-κB, Nrf2/Keap1, NLRP3, PI3K/Akt/mTOR, and the ferroptosis regulatory axis GPX4/SLC7A11 were noted to have the highest-priority pleiotropic hub targets. The computational evidence for quercetin, resveratrol, curcumin, and berberine, as benchmark pleiotropic candidates, was further reviewed, alongside computational drug repurposing analyses. This approach is, however, not without critical limitations. Unlike fields such as oncology, there is sparse IRI-specific omics data and a gap in experimental validation of putative pharmacological candidates. Going forward, emphasis needs to be placed on experimental validation of pleiotropic candidates .