Virtual screening and experimental validation of luteolin cocrystals for enhanced solubility

Luteolin, a bioactive flavonoid known for its anti-inflammatory, antioxidant, and anticancer properties, is limited in its clinical application due to poor water solubility and low bioavailability. In this study, we applied an integrated approach combining virtual screening and experimental validation to identify potential coformers that can form cocrystals with luteolin, improving its physicochemical properties. A total of 28 coformers were analyzed using virtual screening, with predictions based on hydrogen bond strength. From this, 12 promising coformers were selected for experimental trials. Our experimental results led to the successful synthesis of five novel luteolin cocrystals with 4,4′-bipyridine, l -ascorbic acid, nicotinic acid, and isonicotinic acid. Notably, the coformers that formed cocrystals in the experiments ranked highly in the virtual screening results, demonstrating the feasibility of the virtual cocrystal screening method. Notably, all synthesized cocrystals exhibited substantially enhanced solubility profiles, achieving a maximum 4.51-fold increase in solubility relative to pure luteolin. These findings not only validate the virtual screening approach but also highlight its potential applications in pharmaceutical cocrystal design to overcome solubility and bioavailability challenges in drug development.