Structure-based multi-ligand molecular modeling to predict the synergistic effects of limonin and obacunone from Simiao pill against nitric oxide synthase 3 associated with hyperuricemia

Abstract

Hyperuricemia (HUA) mainly occurs because of purine metabolism disorders. We recently proposed that limonin from Simiao pill may have therapeutic effects on nitric oxide synthase 3 (NOS3) that is related to HUA. Concurrently, our previous work employed a new method, structure-based multi-ligand molecular modeling, to identify potential agents from a herbal formula that may produce synergistic effects and may have the potential to develop combination drugs. Therefore, we employed multi-ligand modeling to seek compounds with potential synergistic effects with limonin against NOS3. We obtained 403 multi-ligand docking results between 403 compounds and the limonin-NOS3 complex (average affinity –8.297 kcal/mol). Then we selected the top 10 highest binding affinity compounds for virtual pharmacokinetic and toxicity screening and we found that only obacunone passed all filters. We further subjected obacunone, bound to limonin and NOS3, to molecular dynamics simulations. We found that the NOS3-limonin-obacunone complex was more stable than the NOS3-limonin complex, based on the root mean square deviation of backbone Cα atoms and root mean square fluctuation, which suggests that synergistic effects may exist between limonin and obacunone. Further cell and animal experimental research is required to verify our results.