Structure-based identification of compounds with potential as selective BLT1 antagonists.

The pro-inflammatory molecule leukotriene B4 binds to the leukotriene B4 receptors 1 and 2 (BLT1 and BLT2). Although BLT1 has potential as a target for treating inflammatory diseases, no selective BLT1 antagonist has been marketed to date. Most of the developed compounds bind to both BLT receptors, which are now considered to have some opposite functions. Our goal was to identify potential selective antagonists of BLT1 that could be advanced in future studies for the treatment of inflammatory conditions. We performed a robust virtual screening process using a library of bioactive compounds. The library was screened against BLT1 first, and the top hits were then screened against BLT2. The top eight candidates were selected based on several criteria for further studies, starting with predictions of various physicochemical, pharmacokinetic, and toxicity properties. Next, each selected compound underwent a 500 ns molecular dynamics simulation to evaluate ligand-protein complex stability and the interaction profile. Finally, the compounds were ranked based on predicted binding affinities by calculating their binding free energies. Three hits showed ligand-protein stability in MD simulations, maintained essential interactions, and showed lower binding free energies than the reference compound, indicating they may be more potent BLT1 antagonists. The three identified candidates have unique scaffolds and show potential as potent and selective BLT1 antagonists. These findings pave the way for future experimental evaluation to advance these compounds as anti-inflammatory agents.