Structure-Guided Identification of GPR84 Ligand Candidates With Potential Immunomodulatory Activities.

GPR84, a medium-chain fatty acid (MCFA)-sensing G protein-coupled receptor, plays a significant role in immune regulation. Despite its therapeutic potential, structurally diverse and well-characterized chemical probes of GPR84 remain limited. In the current study, we developed a novel structure-guided and dual-route pipeline to explore and prioritize small-molecule scaffolds compatible with the GPR84 orthosteric pocket, with pharmacophore-based ZINC screening and LigBuilder-based de novo design, accompanied by molecular docking, ADME filtering, and molecular dynamics, followed by immunoregulatory activity validation. ZINC screening identified ZINC149375 (SC787) and ZINC76994316 (Z109), which were further evaluated by 500-ns molecular dynamics simulations. Additionally, LIG081 and LIG133 from the LigBuilder-derived series emerged as computationally prioritized de novo candidates with favorable and persistent predicted interactions within the GPR84 orthosteric pocket. These ZINC-derived compounds demonstrated potent immune cell-dependent immunomodulatory activities associated with GPR84 functional agonism. SC787 and Z109 promote proinflammatory signaling in macrophages while suppressing activation and effector cytokine production in activated CD8+ T cells. Collectively, this study identifies structurally prioritized GPR84 pocket-compatible scaffolds for future receptor-focused immunological activity validation and medicinal chemistry optimization.