SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug dev...SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug development,drug repositioning may be the only solution to the epidemic of sudden infectious diseases.We systematically analyzed all the proteins encoded by SARS-CoV-2 genes,compared them with proteins from other coronavirnses,predicted their structures,and built 19 structures that could be done by homology modeling.By performing target-based virtual ligand screening,a total of21 targets(including two human targets)were screened against compound libraries including ZINC drug database and our own database of natural products.Structure and screening results of important targets such as 3-chymotrypsin-like protease(3 CLpro),Spike,RNA-dependent RNA polymerase(RdRp),and papain like protease(PLpro)were discussed in detail.In addition,a database of 78 commonly used antiviral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed.Possible targets of these compounds and potential drugs acting on a certain target were predicted.This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2,new insights for those drugs currently ongoing clinical studies,and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.展开更多
细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生,故CDK1近年来已成为一个理想的治疗靶点.本文以细胞分裂调控蛋白2的同源体为模板,同源模建了CDK1的结构,并与靛玉红类小分子抑制剂进行分子对接.分别运用三种叠合...细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生,故CDK1近年来已成为一个理想的治疗靶点.本文以细胞分裂调控蛋白2的同源体为模板,同源模建了CDK1的结构,并与靛玉红类小分子抑制剂进行分子对接.分别运用三种叠合方法进行分子叠合,并在此基础上采用Sybyl 7.1中的比较分子场分析(CoMFA)模块及Discovery Studio 3.0中的三维定量构效关系(3D-QSAR)模块(以下简称为DS)分别建立了3D-QSAR模型.其中,将分子对接叠合与公共骨架叠合联合运用的叠合方法所得3D-QSAR模型的评价参数是最佳的(CoMFA:q2=0.681,r2=0.909,r2pred.=0.836;DS:q2=0.579,r2=0.971,r2pred.=0.795,其中q2为交叉验证系数,r2为非交叉验证系数).本文的研究结果在对靛玉红类小分子进行结构修饰设计出新的CDK1抑制剂方面,可提供重要的理论基础.展开更多
AIM:To evaluate the suitability of rupintrivir against Enterovirus 71(EV71)induced severe clinical symptoms using computational methods. METHODS:The structure of EV71 3C protease was predicted by homology modeling.The...AIM:To evaluate the suitability of rupintrivir against Enterovirus 71(EV71)induced severe clinical symptoms using computational methods. METHODS:The structure of EV71 3C protease was predicted by homology modeling.The binding free energies between rupintrivir and EV71 3C and human rhinovirus 3C protease were computed by molecular dynamics and molecular mechanics Poisson-Boltzmann/ surface area and molecular mechanics generalized-born/ surface area methods.EV71 3C fragments obtained from clinical samples collected during May to July 2008 in Shanghai were amplified by reverse-transcription and polymerase chain reaction and sequenced. RESULTS:We observed that rupintrivir had favorable binding affinity with EV71 3C protease(-10.76 kcal/mol). The variability of the 3C protein sequence in isolates of various outbreaks,including those obtained in our hospital from May to July 2008,were also analyzed to validate the conservation of the drug binding pocket. CONCLUSION:Rupintrivir,whose safety profiles had been proved,is an attractive candidate and can be quickly utilized for treating severe EV71 infection.展开更多
基金support from National Mega-project for Innovative Drugs(grant number 2019ZX09721001-004-007,China)National Natural Science Foundation of China(NSFC,grant numbers U1803122,81773637,81773594,and U1703111)the Fundamental Research Fund for the Central Universities(HUST COVID-19 Rapid Response Call,No.2020kfyXGYJ037,China)
文摘SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug development,drug repositioning may be the only solution to the epidemic of sudden infectious diseases.We systematically analyzed all the proteins encoded by SARS-CoV-2 genes,compared them with proteins from other coronavirnses,predicted their structures,and built 19 structures that could be done by homology modeling.By performing target-based virtual ligand screening,a total of21 targets(including two human targets)were screened against compound libraries including ZINC drug database and our own database of natural products.Structure and screening results of important targets such as 3-chymotrypsin-like protease(3 CLpro),Spike,RNA-dependent RNA polymerase(RdRp),and papain like protease(PLpro)were discussed in detail.In addition,a database of 78 commonly used antiviral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed.Possible targets of these compounds and potential drugs acting on a certain target were predicted.This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2,new insights for those drugs currently ongoing clinical studies,and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
文摘细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生,故CDK1近年来已成为一个理想的治疗靶点.本文以细胞分裂调控蛋白2的同源体为模板,同源模建了CDK1的结构,并与靛玉红类小分子抑制剂进行分子对接.分别运用三种叠合方法进行分子叠合,并在此基础上采用Sybyl 7.1中的比较分子场分析(CoMFA)模块及Discovery Studio 3.0中的三维定量构效关系(3D-QSAR)模块(以下简称为DS)分别建立了3D-QSAR模型.其中,将分子对接叠合与公共骨架叠合联合运用的叠合方法所得3D-QSAR模型的评价参数是最佳的(CoMFA:q2=0.681,r2=0.909,r2pred.=0.836;DS:q2=0.579,r2=0.971,r2pred.=0.795,其中q2为交叉验证系数,r2为非交叉验证系数).本文的研究结果在对靛玉红类小分子进行结构修饰设计出新的CDK1抑制剂方面,可提供重要的理论基础.
基金Supported by Start-up Fund(No.KSF0062)of the Shanghai Public Health Clinical Center
文摘AIM:To evaluate the suitability of rupintrivir against Enterovirus 71(EV71)induced severe clinical symptoms using computational methods. METHODS:The structure of EV71 3C protease was predicted by homology modeling.The binding free energies between rupintrivir and EV71 3C and human rhinovirus 3C protease were computed by molecular dynamics and molecular mechanics Poisson-Boltzmann/ surface area and molecular mechanics generalized-born/ surface area methods.EV71 3C fragments obtained from clinical samples collected during May to July 2008 in Shanghai were amplified by reverse-transcription and polymerase chain reaction and sequenced. RESULTS:We observed that rupintrivir had favorable binding affinity with EV71 3C protease(-10.76 kcal/mol). The variability of the 3C protein sequence in isolates of various outbreaks,including those obtained in our hospital from May to July 2008,were also analyzed to validate the conservation of the drug binding pocket. CONCLUSION:Rupintrivir,whose safety profiles had been proved,is an attractive candidate and can be quickly utilized for treating severe EV71 infection.
