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Combining AlphaFold with Focused Virtual Library Design in the Development of Novel CCR2 and CCR5 Antagonists.
Khaled Essa1,2, Kian Noorman van der Dussen1, Yao Yao1
1Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands.
Researchers developed novel intracellular allosteric antagonists for chemokine receptors CCR2 and CCR5. This study identified promising compounds for immunomodulation, shifting focus from orthosteric to allosteric drug discovery.
Area of Science:
- Immunology and Pharmacology
- G protein-coupled receptor (GPCR) research
- Drug discovery and medicinal chemistry
Background:
- Chemokine receptors CCR2 and CCR5 are vital for immune homeostasis.
- Their overactivation links to immunopathologies and cancer.
- Intracellular allosteric modulators offer an underexplored therapeutic avenue.
Purpose of the Study:
- To develop novel intracellular allosteric antagonists for CCR2 and CCR5.
- To explore a paradigm shift from orthosteric to allosteric modulation.
- To identify lead compounds for potential immunomodulatory therapies.
Main Methods:
- Virtual screening of a combinatorial library using molecular docking.
- Utilized a refined AlphaFold model of CCR5 based on CCR2 crystal structure.
- In-house synthesis and experimental evaluation of 18 analogues for CCR2 and CCR5 binding and inhibition.
Main Results:
- Identified several virtual hits through docking.
- Synthesized and tested 18 analogues.
- Discovered 3 CCR2 hits (Ki = 1.3–6 μM) and 1 CCR5 hit (IC50 = 10.8 μM).
Conclusions:
- Successfully developed novel CCR2 and CCR5 intracellular allosteric antagonists.
- Established structure-activity relationships for future drug development.
- Demonstrated an efficient workflow from virtual screening to compound evaluation.
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