Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snak...Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.展开更多
Objective: In folk and TCM clinical medicine, Chinese herbal medicine is used to treat snakebite and has good curative effect, but its active ingredients and mechanism are still unclear. In this study, virtual screeni...Objective: In folk and TCM clinical medicine, Chinese herbal medicine is used to treat snakebite and has good curative effect, but its active ingredients and mechanism are still unclear. In this study, virtual screening and mechanism analysis of effective components from 6 Chinese herbs to inhibit phospholipase A2 of Deinagkistrodon acutus (dPLA2) venom were conducted. Methods: With advanced computing software AutoDock, Pymol and GROMACS, the molecules selected from the Chinese herbal Medicine Chemical Composition databas6e (TCMSP) were docked with the dPLA2 from the protein database (PDB). Further molecular dynamics simulation was used to evaluate the molecular binding stability. Results: Four potential dPLA2-inhibiting molecules were screened: lobelanidine, lobeline, norlobelanine and pratensein, by analyzing the spatial structure, binding energy and binding interaction of small molecular-dPLA2 complexes, as well as the RMSD and RMSF of molecular dynamics simulation. Conclusion: To our knowledge, this is the first report of lobeline has an inhibitory effect on dPLA2, and lobelanidine, as a precursor of lobeline, has a stronger inhibitory effect. According to the docking results, it is speculated that the mechanism of action of the four molecules is to form stable interactions with calcium ions and amino acid residues on the calcium ion binding ring in dPLA2. Moreover, these small molecules compete with phosphatidylcholine (the natural substrate of dPLA2) to bind dPLA2 and have a higher affinity than phosphatidylcholine, resulting in inhibition of dPLA2 activity.展开更多
文摘Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.
文摘Objective: In folk and TCM clinical medicine, Chinese herbal medicine is used to treat snakebite and has good curative effect, but its active ingredients and mechanism are still unclear. In this study, virtual screening and mechanism analysis of effective components from 6 Chinese herbs to inhibit phospholipase A2 of Deinagkistrodon acutus (dPLA2) venom were conducted. Methods: With advanced computing software AutoDock, Pymol and GROMACS, the molecules selected from the Chinese herbal Medicine Chemical Composition databas6e (TCMSP) were docked with the dPLA2 from the protein database (PDB). Further molecular dynamics simulation was used to evaluate the molecular binding stability. Results: Four potential dPLA2-inhibiting molecules were screened: lobelanidine, lobeline, norlobelanine and pratensein, by analyzing the spatial structure, binding energy and binding interaction of small molecular-dPLA2 complexes, as well as the RMSD and RMSF of molecular dynamics simulation. Conclusion: To our knowledge, this is the first report of lobeline has an inhibitory effect on dPLA2, and lobelanidine, as a precursor of lobeline, has a stronger inhibitory effect. According to the docking results, it is speculated that the mechanism of action of the four molecules is to form stable interactions with calcium ions and amino acid residues on the calcium ion binding ring in dPLA2. Moreover, these small molecules compete with phosphatidylcholine (the natural substrate of dPLA2) to bind dPLA2 and have a higher affinity than phosphatidylcholine, resulting in inhibition of dPLA2 activity.
