THREE-DIMENSIONAL SHAPE SIMILARITY APPROACH FOR THE DISCOVERY OF IL-1R1 RECEPTOR INHIBITORS

Interleukin-1β (IL-1β) is a prototypical cytokine of the IL-1 family that regulates innate and adaptive immunity. Its cognate receptor, interleukin-1 receptor type 1 (IL-1R1), is therefore a tractable target for anti-inflammatory drug discovery. The peptide antagonist AF10847 binds IL-1R1 and disrupts the IL-1β/IL-1R1 protein–protein interface, validating the receptor’s druggability. However, its peptidic nature entails poor oral bioavailability and unfavorable developability. This study aimed to discover non-peptidic small molecules capable of inhibiting IL-1R1 using a 3D shape-similarity strategy anchored on AF10847. The IL-1R1/AF10847 co-crystal structure was prepared for modeling, and the binding pocket was delineated using FPocket, DoGSiteScorer, and DeepSite. In silico alanine scanning of the complex identified interaction “hot spots” at the protein-protein interface. Following comprehensive conformer enumeration of AF10847, a ROCS query capturing its molecular envelope and salient pharmacophoric features was constructed and deployed to virtually screen large purchasable libraries (Enamine, ChemDiv, Asinex and NCI Open Database). Candidates were ranked by Tanimoto similarity score and lightly filtered for drug-likeness prior to structure-based triage. Top-ranked molecules underwent ensemble molecular docking into multiple IL-1R1 conformations to accommodate receptor flexibility, with poses assessed by consensus scoring and interaction-fingerprint analysis for consistency with the AF10847 recognition pattern. Short all-atom molecular-dynamics simulations were then performed to evaluate pose stability via heavy-atom RMSD and hydrogen-bond occupancy and to obtain qualitative affinity estimates using trajectory-averaged metrics. This computational cascade identified several chemically diverse small-molecule candidates predicted to engage IL-1R1 in persistent, well-packed poses with favorable interaction networks. These in silico hits constitute tractable starting points for experimental validation, including biochemical binding assays and cellular readouts of IL-1β signaling, orthogonal selectivity counterscreens early ADMET profiling to guide medicinal-chemistry optimization toward orally available IL-1R1 modulators.