Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of dr...Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of drug research and development(R&D).With the advancement of experimental technology and computer hardware,artificial intelligence(AI)has recently emerged as a leading tool in analyzing abundant and high-dimensional data.Explosive growth in the size of biomedical data provides advantages in applying AI in all stages of drug R&D.Driven by big data in biomedicine,AI has led to a revolution in drug R&D,due to its ability to discover new drugs more efficiently and at lower cost.This review begins with a brief overview of common AI models in the field of drug discovery;then,it summarizes and discusses in depth their specific applications in various stages of drug R&D,such as target discovery,drug discovery and design,preclinical research,automated drug synthesis,and influences in the pharmaceutical market.Finally,the major limitations of AI in drug R&D are fully discussed and possible solutions are proposed.展开更多
Computer networks face a variety of cyberattacks.Most network attacks are contagious and destructive,and these types of attacks can be harmful to society and computer network security.Security evaluation is an effecti...Computer networks face a variety of cyberattacks.Most network attacks are contagious and destructive,and these types of attacks can be harmful to society and computer network security.Security evaluation is an effective method to solve network security problems.For accurate assessment of the vulnerabilities of computer networks,this paper proposes a network security risk assessment method based on a Bayesian network attack graph(B_NAG)model.First,a new resource attack graph(RAG)and the algorithm E-Loop,which is applied to eliminate loops in the B_NAG,are proposed.Second,to distinguish the confusing relationships between nodes of the attack graph in the conversion process,a related algorithm is proposed to generate the B_NAG model.Finally,to analyze the reachability of paths in B_NAG,the measuring indexs such as node attack complexity and node state transition are defined,and an iterative algorithm for obtaining the probability of reaching the target node is presented.On this basis,the posterior probability of related nodes can be calculated.A simulation environment is set up to evaluate the effectiveness of the B_NAG model.The experimental results indicate that the B_NAG model is realistic and effective in evaluating vulnerabilities of computer networks and can accurately highlight the degree of vulnerability in a chaotic relationship.展开更多
The rapid progress of the Internet has exposed networks to an increasednumber of threats. Intrusion detection technology can effectively protect networksecurity against malicious attacks. In this paper, we propose a R...The rapid progress of the Internet has exposed networks to an increasednumber of threats. Intrusion detection technology can effectively protect networksecurity against malicious attacks. In this paper, we propose a ReliefF-P-NaiveBayes and softmax regression (RP-NBSR) model based on machine learningfor network attack detection to improve the false detection rate and F1 score ofunknown intrusion behavior. In the proposed model, the Pearson correlation coef-ficient is introduced to compensate for deficiencies in correlation analysis betweenfeatures by the ReliefF feature selection algorithm, and a ReliefF-Pearson correlation coefficient (ReliefF-P) algorithm is proposed. Then, the Relief-P algorithm isused to preprocess the UNSW-NB15 dataset to remove irrelevant features andobtain a new feature subset. Finally, naïve Bayes and softmax regression (NBSR)classifier is constructed by cascading the naïve Bayes classifier and softmaxregression classifier, and an attack detection model based on RP-NBSR is established. The experimental results on the UNSW-NB15 dataset show that the attackdetection model based on RP-NBSR has a lower false detection rate and higherF1 score than other detection models.展开更多
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S31...Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not.展开更多
The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1...The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel disease.In this study,a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug design.Among them,compound 9i was identified as a potent and selective S1PR1 agonist with activities onβ-arrestin recruitment(EC50=0.36 nmol/L)and receptor internalization(EC50=8.09 nmol/L).Meanwhile,compound 9i displayed an oral bioavailability up to 93.6%.Based on its excellent activity to S1PR1 and pharmacokinetic properties,compound 9i effectively alleviated dextran sulfate sodium(DSS)-induced ulcerative colitis in mice at a dose of 0.1 mg/kg.展开更多
CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be ...CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be spelt as‘Dimitri Lavillette’is provided in this correction.OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://creativecommons.org/licenses/by/4.0/.展开更多
Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug de...Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug design and synthesis of macrocycle limit its applications.In this study,a series of macrocyclic derivatives designed from anaplastic lymphoma kinase(ALK)inhibitor lorlatinib were synthesized as Janus kinase 2(JAK2)selective inhibitors.Among them,17f had the best inhibitory activity(IC50=0.177μmol·L^-1)and selectivity for JAK2 over JAK1 and JAK3,which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhihitors.展开更多
Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis...Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis of S312(B)and S416(C).Thermodynamic analysis of the binding of S312 and S416 to DHODH was carried out at 25 C on a MicroCal iTC200 instrument.Kinetic analysis of the binding of S312 and S416 to DHODH was performed with a Biacore T200 instrument.展开更多
Trajectory privacy protection schemes based on suppression strategies rarely take geospatial constraints into account,which is made more likely for an attacker to determine the user’s true sensitive location and traj...Trajectory privacy protection schemes based on suppression strategies rarely take geospatial constraints into account,which is made more likely for an attacker to determine the user’s true sensitive location and trajectory.To solve this problem,this paper presents a privacy budget allocation method based on privacy security level(PSL).Firstly,in a custom map,the idea of P-series is contributed to allocate a given total privacy budget reasonably to the initially sensitive locations.Then,the size of privacy security level for sensitive locations is dynamically adjusted by comparing it with the customized initial level threshold parameterµ.Finally,the privacy budget of the initial sensitive location is allocated to its neighbors based on the relationship between distance and degree between nodes.By comparing the PSL algorithm with the traditional allocation methods,the results show that it is more flexible to allocate a privacy budget without compromising location privacy under the same preset conditions.展开更多
基金funded by the Natural Science Foundation of Zhejiang Province(LR21H300001)National Key R&D Program of China(2022YFC3400501)+4 种基金National Natural Science Foundation of China(22220102001,U1909208,81872798,and 81825020)Leading Talent of the“Ten Thousand Plan”-National High-Level Talents Special Support Plan of ChinaFundamental Research Fund of Central University(2018QNA7023)Key R&D Program of Zhejiang Province(2020C03010)“Double Top-Class”University(181201*194232101)。
文摘Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of drug research and development(R&D).With the advancement of experimental technology and computer hardware,artificial intelligence(AI)has recently emerged as a leading tool in analyzing abundant and high-dimensional data.Explosive growth in the size of biomedical data provides advantages in applying AI in all stages of drug R&D.Driven by big data in biomedicine,AI has led to a revolution in drug R&D,due to its ability to discover new drugs more efficiently and at lower cost.This review begins with a brief overview of common AI models in the field of drug discovery;then,it summarizes and discusses in depth their specific applications in various stages of drug R&D,such as target discovery,drug discovery and design,preclinical research,automated drug synthesis,and influences in the pharmaceutical market.Finally,the major limitations of AI in drug R&D are fully discussed and possible solutions are proposed.
基金This work was partially supported by the National Natural Science Foundation of China(61300216,Wang,H,www.nsfc.gov.cn).
文摘Computer networks face a variety of cyberattacks.Most network attacks are contagious and destructive,and these types of attacks can be harmful to society and computer network security.Security evaluation is an effective method to solve network security problems.For accurate assessment of the vulnerabilities of computer networks,this paper proposes a network security risk assessment method based on a Bayesian network attack graph(B_NAG)model.First,a new resource attack graph(RAG)and the algorithm E-Loop,which is applied to eliminate loops in the B_NAG,are proposed.Second,to distinguish the confusing relationships between nodes of the attack graph in the conversion process,a related algorithm is proposed to generate the B_NAG model.Finally,to analyze the reachability of paths in B_NAG,the measuring indexs such as node attack complexity and node state transition are defined,and an iterative algorithm for obtaining the probability of reaching the target node is presented.On this basis,the posterior probability of related nodes can be calculated.A simulation environment is set up to evaluate the effectiveness of the B_NAG model.The experimental results indicate that the B_NAG model is realistic and effective in evaluating vulnerabilities of computer networks and can accurately highlight the degree of vulnerability in a chaotic relationship.
基金supported by the National Natural Science Foundation of China(61300216,Wang,H,www.nsfc.gov.cn).
文摘The rapid progress of the Internet has exposed networks to an increasednumber of threats. Intrusion detection technology can effectively protect networksecurity against malicious attacks. In this paper, we propose a ReliefF-P-NaiveBayes and softmax regression (RP-NBSR) model based on machine learningfor network attack detection to improve the false detection rate and F1 score ofunknown intrusion behavior. In the proposed model, the Pearson correlation coef-ficient is introduced to compensate for deficiencies in correlation analysis betweenfeatures by the ReliefF feature selection algorithm, and a ReliefF-Pearson correlation coefficient (ReliefF-P) algorithm is proposed. Then, the Relief-P algorithm isused to preprocess the UNSW-NB15 dataset to remove irrelevant features andobtain a new feature subset. Finally, naïve Bayes and softmax regression (NBSR)classifier is constructed by cascading the naïve Bayes classifier and softmaxregression classifier, and an attack detection model based on RP-NBSR is established. The experimental results on the UNSW-NB15 dataset show that the attackdetection model based on RP-NBSR has a lower false detection rate and higherF1 score than other detection models.
基金This work was supported in part by the National Key Research and Development Program Grants(2018FYA0900801 and 2018ZX10101004003001 to K.X.2016YFA0502304 to H.L.)the National Natural Science Foundation of China(Grants 31922004 and 81772202 to K.X.,81825020 to H.L.)+2 种基金the National Science&Technology Major Project"Key New Drug Creation and Manufac-turing Program"of China(Grant 2018ZX09711002 to H.L.)Appli-cation&Frontier Research Program of Wuhan Govemment(2019020701011463 to K.X.).Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young ProfessionalsWe are grateful to Taikang Insurance Group Co,Ltd,Beiing Taikang Yicai Foundation,and Special Fund for COVID-19 Research of Wuhan University for their great supports to this work.
文摘Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not.
基金supported in part by the National Natural Science Foundation of China(grants 81825020 and 82150208 to H.L.)the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project(grants 21S11907900 and 20S11901000 to Z.Z.)the Fundamental Research Funds for the Central Universities.Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.
文摘The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel disease.In this study,a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug design.Among them,compound 9i was identified as a potent and selective S1PR1 agonist with activities onβ-arrestin recruitment(EC50=0.36 nmol/L)and receptor internalization(EC50=8.09 nmol/L).Meanwhile,compound 9i displayed an oral bioavailability up to 93.6%.Based on its excellent activity to S1PR1 and pharmacokinetic properties,compound 9i effectively alleviated dextran sulfate sodium(DSS)-induced ulcerative colitis in mice at a dose of 0.1 mg/kg.
文摘CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be spelt as‘Dimitri Lavillette’is provided in this correction.OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://creativecommons.org/licenses/by/4.0/.
基金The research is supported in part by the National Key Research and Development Program(Grant No.2016YFA0502304)the National Natural Science Foundation of China(Grant No.81825020)+2 种基金the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program",China(No.2018ZX09711002)the Fundamental Research Funds for the Central UniversitiesHonglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and the National Program for Support of Top-Notch Young Professionals.
文摘Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug design and synthesis of macrocycle limit its applications.In this study,a series of macrocyclic derivatives designed from anaplastic lymphoma kinase(ALK)inhibitor lorlatinib were synthesized as Janus kinase 2(JAK2)selective inhibitors.Among them,17f had the best inhibitory activity(IC50=0.177μmol·L^-1)and selectivity for JAK2 over JAK1 and JAK3,which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhihitors.
文摘Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis of S312(B)and S416(C).Thermodynamic analysis of the binding of S312 and S416 to DHODH was carried out at 25 C on a MicroCal iTC200 instrument.Kinetic analysis of the binding of S312 and S416 to DHODH was performed with a Biacore T200 instrument.
基金the National Natural Science Foundation of China.61300216Doctoral Scientific Fund of Henan Polytechnic University.B2022-16+1 种基金Doctoral Scientific Fund of Henan Polytechnic University.B2020-32Youth Fund of Henan Polytechnic University.Q2014-05。
文摘Trajectory privacy protection schemes based on suppression strategies rarely take geospatial constraints into account,which is made more likely for an attacker to determine the user’s true sensitive location and trajectory.To solve this problem,this paper presents a privacy budget allocation method based on privacy security level(PSL).Firstly,in a custom map,the idea of P-series is contributed to allocate a given total privacy budget reasonably to the initially sensitive locations.Then,the size of privacy security level for sensitive locations is dynamically adjusted by comparing it with the customized initial level threshold parameterµ.Finally,the privacy budget of the initial sensitive location is allocated to its neighbors based on the relationship between distance and degree between nodes.By comparing the PSL algorithm with the traditional allocation methods,the results show that it is more flexible to allocate a privacy budget without compromising location privacy under the same preset conditions.
