Identifying Modulators of CXC Receptors 3 and 4 with Tailored Selectivity Using Multi-Target Docking
| Autor: | Regine Brox, Denis Schmidt, Peter Kolb, Nuska Tschammer, Viachaslau Bernat |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Receptors
CXCR4 Receptors CXCR3 Computational biology Pharmacology Biology Ligands Sulfur Radioisotopes CXCR3 Biochemistry Molecular Docking Simulation Protein Structure Secondary Small Molecule Libraries Structure-Activity Relationship Chemokine receptor Drug Discovery Humans Homology modeling Binding site Receptor Binding Sites Drug discovery Cell Membrane General Medicine Protein Structure Tertiary HEK293 Cells Guanosine 5'-O-(3-Thiotriphosphate) Structural Homology Protein Docking (molecular) Molecular Medicine Databases Chemical Protein Binding |
| Zdroj: | ACS Chemical Biology. 10:715-724 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/cb500577j |
| Popis: | The G protein-coupled receptors of the C-X-C subfamily form a group among the chemokine receptors whose endogenous ligands are peptides with a common Cys-X-Cys motif. The CXC chemokine receptors 3 and 4 (CXCR3, CXCR4), which are investigated in this study, are linked to severe diseases such as cancer, multiple sclerosis, and HIV infections. Of particular interest, this receptor pair potentially forms a target for a polypharmacological drug treatment. Considering known ligands from public databases, such dual binders have not been identified yet. We therefore applied large-scale docking to the structure of CXCR4 and a homology model of CXCR3 with the goal to predict such dual binders, as well as compounds selective for either one of the receptors. Using signaling and biochemical assays, we showed that more than 50% of these predictions were correct in each category, yielding ligands with excellent binding efficiencies. These results highlight that docking is a suitable tool for the identification of ligands with tailored binding profiles to GPCRs, even when using homology models. More importantly, we present novel CXCR3-CXCR4 dual modulators that might pave the road to understanding the mechanisms of polypharmacological inhibition of these receptors. |
| Databáze: | OpenAIRE |
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