Similar Binding Mode of a 5-Sulfonylthiouracil Derivative Antagonist at Chemerin Receptors CMKLR1 and GPR1.

Several studies have linked chemerin/chemokine-like receptor 1 (CMKLR1) to inflammation, leukocyte recruitment, and obesity. Reduced cellular activation may reduce inflammation in adipose tissues. High-throughput screening identified a novel antagonist (VU0514009), which was optimized to compound as a full and competitive antagonist (IC = 37 μM). Mutagenesis studies elucidated relevant interactions of compound at CMKLR1 residues Y6.51 and L7.35 as well as F7.31, S7.32, and T7.39 forming the binding pocket. Based on active CMKLR1/chemerin-9 structures and the inactive AlphaFold model, in silico docking was performed in the inactive model, with compound most likely binding orthosterically. Considering the sequence similarity of CMKLR1 and GPR1, compound was docked to GPR1, indicating a similar binding. At GPR1, compound showed a slightly lower effect on chemerin-9-mediated arrestin recruitment and internalization.