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.Concurrentl...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 Cαatoms 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.展开更多
基金This work was funded by the Key Project of National Natural Science Foundation of China[grant number 81830117]Joint Funds of National Natural Science Foundation of China[grant number U22A20365]+3 种基金National Natural Science Foundation of China[grant numbers 8220140209,82274499]Guangdong Basic and Applied Basic Research Foundation[grant number 2021A1515110082]China Postdoctoral Science Foundation[grant number 2022M711534]Science&Technical Plan of Guangzhou,Guangdong,China[grant number 201903010069].
文摘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 Cαatoms 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.
