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

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

  • J Med Chem. 2025 Jun 12;68(11):11149-11173. doi: 10.1021/acs.jmedchem.5c00135.
Tina Schermeng 1,  Alexander Fürll 2,  Fabian Liessmann 2 3,  Lukas von Bredow 2,  Jan Stichel 1,  C David Weaver 4,  Maik Tretbar 2,  Jens Meiler 2 3 4,  Annette G Beck-Sickinger 1
Affiliations

Affiliations

  • 1 Institute of Biochemistry, Leipzig University, Leipzig 04103, Germany.
  • 2 Institute for Drug Discovery, Leipzig University, Leipzig 04103, Germany.
  • 3 Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI and School of Embedded Composite Artificial Intelligence SECAI, Leipzig 04105, Germany.
  • 4 Department of Chemistry, Department of Pharmacology and Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States.
PMID: 40377914 DOI: 10.1021/acs.jmedchem.5c00135
Abstract

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.

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