AbstractInterleukine-1 family cytokines are key orchestrators of innate and adaptive immunity. In particular, up-regulation of IL-1R1 via its agonistic ligands consisting of IL-1β and IL-1α is implicated in a variety of human diseases, such as rheumatoid arthritis, psoriasis, type I diabetes, amyotrophic lateral sclerosis, and dry-eye disease. Until now, there are no small-molecule inhibitors of the IL-1R1 with increased antagonistic potency to be used for the treatment of peripheral inflammation. The objective of this study was to engineer a low-molecular-weight version of IL-1RA with increased affinity and enhanced antagonistic activity for potential therapeutic use. To develop a smaller protein–ligand with a better affinity to IL-1R, we used bioinformatics studies and in silico simulations to anticipate non-binding areas on IL-1RA. In this study, we have identified a 41aa (F57-F98) non-binding site of IL-1RA. Overall RMSF of the Truncated complex (1.5 nm) was lower than the Native complex (2 nm), which could prove higher stability of the Truncated complex. The free binding energy of the T-IL-1RA (− 1087.037 kJ/mol) was significantly lower than the IL-1RA (− 836.819 kJ/mol) which could demonstrate a higher binding affinity of the truncated ligand with its receptor as a result of new important interactions. These findings have demonstrated a higher binding affinity of the T-IL-1RA with its receptor than the native protein. These results should: have an impact on the development of new treatments that block IL-1 signaling, although more research is needed in vitro and in vivo.