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
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.
