Docking for EP4R antagonists active against inflammatory pain

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Prostaglandin E2 (PGE2) is a lipid mediator of inflammatory pain via G protein-coupled receptors like EP4R.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis but can cause adverse effects.
• Selective EP4R antagonists offer a targeted anti-inflammatory strategy, but none are currently approved.

Purpose of the Study:

• To discover and develop novel, selective EP4R antagonists.
• To diversify the chemical scaffolds of EP4R antagonists.
• To identify compounds with potential therapeutic applications for inflammatory pain.

Main Methods:

• Computational docking of over 400 million compounds against an EP4R crystal structure.
• Experimental validation and de novo synthesis of 71 highly ranked compounds.
• Structure-based optimization to enhance potency and selectivity.

Main Results:

• Identification of a potent and selective EP4R antagonist with 16 nM potency.
• Demonstration of favorable pharmacokinetics for the discovered compound.
• Validation of anti-allodynic and anti-inflammatory activity in preclinical pain models.

Conclusions:

• Novel EP4R antagonists were identified through computational screening and structure-based optimization.
• The discovered compound exhibits potent anti-inflammatory and anti-allodynic effects.
• This work provides a promising lead for developing new treatments for inflammatory pain.