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 16 as a full and competitive antagonist (IC50 = 37 μM). Mutagenesis studies elucidated relevant
interactions of compound 16 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 16 most likely binding orthosterically. Considering
the sequence similarity of CMKLR1 and GPR1, compound 16 was docked to GPR1, indicating a similar binding. At GPR1, compound 16 showed a slightly lower effect on chemerin-9-mediated arrestin
recruitment and internalization.