Ryanodine receptors (RyR) are the major Ca2+ release channels in both cardiac and skeletal muscle, they play a crucial role in the Ca2+ signaling pathway that govern the
This study aimed to elucidate the inhibition mechanism of apigenin against porcine pancreatic lipase(PPL),and,moreover,to comprehensively reveal the molecular basis of its anti-obesity via network pharmacology approac...This study aimed to elucidate the inhibition mechanism of apigenin against porcine pancreatic lipase(PPL),and,moreover,to comprehensively reveal the molecular basis of its anti-obesity via network pharmacology approach.The results showed that apigenin inhibited PPL with an IC50 value of 0.377±0.041 mM.Spectroscopic techniques combined molecular docking suggested that apigenin could bind into the PPL active pocket,affecting its normal spatial conformation.Moreover,molecular dynamic(MD)simulations revealed that the open conformation of PPL tended to transit to the closed in the presence of apigenin,which might one important reason for the inhibition of PPL catalytic ability.Network pharmacology analysis revealed that a total of 49 proteins could be identified as potential targets for the anti-obesity effects of apigenin.According to the protein-protein interaction(PPI)network analysis,six hub targets were extracted including IGF1,ESR1,MMP9,PPARA,MAPK14 and NR3C1.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment indicated that the 49 potential targets could be mapped to 30 pathways(p<0.05).Among them,PI3K-Akt signaling pathway and insulin resistance can be considered as two major pathways regulated by apigenin.Further docking studies indicated that apigenin can bind into the binding pocket of the six hub target proteins identified according to the PPI network.The results indicated that in addition to inhibiting PPL,apigenin could exhibit anti-obesity benefit through the molecular mechanisms uncovered by network pharmacology.This study proposes a new strategy to reveal the mechanisms of dietary polyphenols at the level of network pharmacology.展开更多
HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investiga...HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investigation of the mechanism of HDAC8 inhibitions containing hydroxamic acid group. Compound 1 with high activity and compound 2 with low activity were selected for comparative study. Compound 1 formed a stronger chelation with Zn ion and was more stable in the HDAC8 pocket than compound 2. Residues HIS-180, ASP-178, ASP-267, and GLY-140 played a critical role in securing the position of compound 1. Both the head and tail of compound 1 formed strong hydrogen bonds with ASP-178, facilitating the ZBG of compound 1 close to the Zn ion so that they formed permanent chelation during the simulation period. The Cap group of the compounds with branch and long chains was advantageous to form interaction with active pocket opening. What’s more, based on the results of this study, three innovative recommendations for the design of highly active HDAC8 inhibitors were presented, which will be useful for the development of new HDAC8 inhibitors.展开更多
文摘Ryanodine receptors (RyR) are the major Ca2+ release channels in both cardiac and skeletal muscle, they play a crucial role in the Ca2+ signaling pathway that govern the
基金supported by[National Natural Science Foundation of China](Grant number 32001702).
文摘This study aimed to elucidate the inhibition mechanism of apigenin against porcine pancreatic lipase(PPL),and,moreover,to comprehensively reveal the molecular basis of its anti-obesity via network pharmacology approach.The results showed that apigenin inhibited PPL with an IC50 value of 0.377±0.041 mM.Spectroscopic techniques combined molecular docking suggested that apigenin could bind into the PPL active pocket,affecting its normal spatial conformation.Moreover,molecular dynamic(MD)simulations revealed that the open conformation of PPL tended to transit to the closed in the presence of apigenin,which might one important reason for the inhibition of PPL catalytic ability.Network pharmacology analysis revealed that a total of 49 proteins could be identified as potential targets for the anti-obesity effects of apigenin.According to the protein-protein interaction(PPI)network analysis,six hub targets were extracted including IGF1,ESR1,MMP9,PPARA,MAPK14 and NR3C1.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment indicated that the 49 potential targets could be mapped to 30 pathways(p<0.05).Among them,PI3K-Akt signaling pathway and insulin resistance can be considered as two major pathways regulated by apigenin.Further docking studies indicated that apigenin can bind into the binding pocket of the six hub target proteins identified according to the PPI network.The results indicated that in addition to inhibiting PPL,apigenin could exhibit anti-obesity benefit through the molecular mechanisms uncovered by network pharmacology.This study proposes a new strategy to reveal the mechanisms of dietary polyphenols at the level of network pharmacology.
基金Talents Introduction Foundation for Universities of Guangdong Province(GD 2011)the Science and Technology Planning Project of Guangzhou(No.2013J4100071)。
文摘HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investigation of the mechanism of HDAC8 inhibitions containing hydroxamic acid group. Compound 1 with high activity and compound 2 with low activity were selected for comparative study. Compound 1 formed a stronger chelation with Zn ion and was more stable in the HDAC8 pocket than compound 2. Residues HIS-180, ASP-178, ASP-267, and GLY-140 played a critical role in securing the position of compound 1. Both the head and tail of compound 1 formed strong hydrogen bonds with ASP-178, facilitating the ZBG of compound 1 close to the Zn ion so that they formed permanent chelation during the simulation period. The Cap group of the compounds with branch and long chains was advantageous to form interaction with active pocket opening. What’s more, based on the results of this study, three innovative recommendations for the design of highly active HDAC8 inhibitors were presented, which will be useful for the development of new HDAC8 inhibitors.
