Optimization of MrgX2 Antagonists Based on the "Cell Membrane Chromatography-Molecular Docking" Approach

Area of Science:

• Pharmacology and Drug Discovery
• Biochemistry and Biophysics
• Computational Chemistry

Background:

• Molecular docking is a key technique in drug discovery for predicting ligand-receptor interactions.
• Accurate affinity data is crucial for refining molecular docking predictions.
• Cell membrane chromatography (CMC) is a biomimetic method for evaluating ligand-membrane receptor affinity.

Purpose of the Study:

• To develop an integrated approach combining CMC and molecular docking for optimizing MrgX2 antagonists.
• To design and validate a novel computational method for enhancing drug discovery efficiency.

Main Methods:

• Development of the "Kd-r_psp_MMGBSA_dG_Bind_Lipo" approach, integrating CMC with molecular docking.
• Design and synthesis of novel compounds based on the developed computational approach.
• In vitro and in vivo evaluation of the synthesized compounds as MrgX2 antagonists.

Main Results:

• The integrated approach successfully optimized MrgX2 antagonists.
• Compound BER-5 was designed, synthesized, and identified as a potent MrgX2 antagonist.
• BER-5 demonstrated significant antiallergic effects in both in vitro and in vivo models.

Conclusions:

• The integrated CMC and molecular docking approach is a rational and effective strategy for optimizing MrgX2 antagonists.
• This method shows potential for broader applications in drug development, particularly for G protein-coupled receptors (GPCRs) on cell membranes.
• The successful design of BER-5 validates the utility of this approach in discovering novel therapeutic agents.