Inflammation is an important mediator of both the innate and adaptive immune responses. However, it can be a “double-edged sword” as dysregulation of IL-1-mediated inflammation, for example, is known to cause several autoimmune and autoinflammatory diseases. A large body of pre-clinical and clinical evidence corelates IL-1 inhibition to decreased disease severity for several tested conditions – highlighting the therapeutic importance of the IL-1 pathway (Dinarello et al., 2012). Methotrexate, Ibuprofen, high-dose aspirin, and prednisone exists as first line anti-inflammatory drugs, however, they are strongly associated with severe adverse effects including bleeding, hypertension, and cancers, amongst others. Protein-based biologics IL-1 blockades are also used to overcome the limitations of first line drugs, but they are also expensive, unstable, and dependent on refrigeration for storage. Small molecules on the other hand, although difficult to design for the large and flat protein-protein interaction surfaces like that of IL1β – IL1RI complex, do have more benefits over biologics as they are easier to synthesize, cheaper to produce, relatively more stable, and are less dependent on cold chain storage. Unfortunately, to the best of our knowledge, no small molecule anti-IL1 agent currently exist. In this proposal, we aim to identify small anti-IL-1 blockers via virtual screening and biophysical techniques. The Fraternali’s group in collaboration with the De Nicola’s group, solved the crystal structures of a set of fragments with strong affinity for the IL-1 interface. We use the structures as starting point for screening the US FDA approved drugs and an AI (Cyclica Inc) pre-screened datasets against pocket-3 of IL-1. Consequently, 13 FDA drugs and 7 Cyclica Inc. compounds make the hit list as potential IL-1 inhibitors. We now aim to perform NMR spectroscopy and ITC assays to assess binding affinity between the hits and IL-1 target.