Drug target relationship(DTR)prediction is a rapidly evolving area of research in com-putational drug discovery.Despite recent advances in computational solutions that have overcome the challenges of in vitro and in v...Drug target relationship(DTR)prediction is a rapidly evolving area of research in com-putational drug discovery.Despite recent advances in computational solutions that have overcome the challenges of in vitro and in vivo experiments,most computational methods still focus on binary classification.They ignore the importance of binding affinity,which correctly distinguishes between on-targets and off-targets.In this study,we propose a deep learning model based on the microstruc-ture of compounds and proteins to predict drug-target binding affinity(DTA),which utilizes topo-logical structure information of drug molecules and sequence semantic information of proteins.In this model,graph attention network(GAT)is used to capture the deep features of the compound molecular graph,and bidirectional long short-term memory(BiLSTM)network is used to extract the protein sequence features,and the pharmacological context of DTA is obtained by combining the two.The results show that the proposed model has achieved superior performance in both cor-rectly predicting the value of interaction strength and correctly discriminating the ranking of bind-ing strength compared to the state-of-the-art baselines.A case study experiment on COVID-19 con-firms that the proposed DTA model can be used as an effective pre-screening tool in drug discovery.展开更多
Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve dru...Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas:(1) inhaled drug-aerosol delivery into human lung-airways; and(2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well.Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system.展开更多
Background:Computational approaches for accurate prediction of drug interactions,such as drug-drug interactions(DDIs)and drug-target interactions(DTIs),are highly demanded for biochemical researchers.Despite the fact ...Background:Computational approaches for accurate prediction of drug interactions,such as drug-drug interactions(DDIs)and drug-target interactions(DTIs),are highly demanded for biochemical researchers.Despite the fact that many methods have been proposed and developed to predict DDIs and DTIs respectively,their success is still limited due to a lack of systematic evaluation of the intrinsic properties embedded in the corresponding chemical structure.Methods:In this paper,we develop DeepDrug,a deep learning framework for overcoming the above limitation by using residual graph convolutional networks(Res-GCNs)and convolutional networks(CNNs)to learn the comprehensive structure-and sequence-based representations of drugs and proteins.Results:DeepDrug outperforms state-of-the-art methods in a series of systematic experiments,including binary-class DDIs,multi-class/multi-label DDIs,binary-class DTIs classification and DTIs regression tasks.Furthermore,we visualize the structural features learned by DeepDrug Res-GCN module,which displays compatible and accordant patterns in chemical properties and drug categories,providing additional evidence to support the strong predictive power of DeepDrug.Ultimately,we apply DeepDrug to perform drug repositioning on the whole DrugBank database to discover the potential drug candidates against SARS-CoV-2,where 7 out of 10 top-ranked drugs are reported to be repurposed to potentially treat coronavirus disease 2019(COVID-19).Conclusions:To sum up,we believe that DeepDrug is an efficient tool in accurate prediction of DDIs and DTIs and provides a promising insight in understanding the underlying mechanism of these biochemical relations.展开更多
Predicting interactions between drugs and target proteins has become an essential task in the drug discovery process.Although the method of validation via wet-lab experiments has become available,experimental methods ...Predicting interactions between drugs and target proteins has become an essential task in the drug discovery process.Although the method of validation via wet-lab experiments has become available,experimental methods for drug-target interaction(DTI)identification remain either time consuming or heavily dependent on domain expertise.Therefore,various computational models have been proposed to predict possible interactions between drugs and target proteins.However,most prediction methods do not consider the topological structures characteristics of the relationship.In this paper,we propose a relational topologybased heterogeneous network embedding method to predict drug-target interactions,abbreviated as RTHNE_DTI.We first construct a heterogeneous information network based on the interaction between different types of nodes,to enhance the ability of association discovery by fully considering the topology of the network.Then drug and target protein nodes can be represented by the other types of nodes.According to the different topological structure of the relationship between the nodes,we divide the relationship in the heterogeneous network into two categories and model them separately.Extensive experiments on the realworld drug datasets,RTHNE_DTI produces high efficiency and outperforms other state-of-the-art methods.RTHNE_DTI can be further used to predict the interaction between unknown interaction drug-target pairs.展开更多
Many efforts have been exerted toward screening potential drugs for targets,and conducting wet experiments remains a laborious and time-consuming approach.Artificial intelligence methods,such as Convolutional Neural N...Many efforts have been exerted toward screening potential drugs for targets,and conducting wet experiments remains a laborious and time-consuming approach.Artificial intelligence methods,such as Convolutional Neural Network(CNN),are widely used to facilitate new drug discovery.Owing to the structural limitations of CNN,features extracted from this method are local patterns that lack global information.However,global information extracted from the whole sequence and local patterns extracted from the special domain can influence the drugtarget affinity.A fusion of global information and local patterns can construct neural network calculations closer to actual biological processes.This paper proposes a Fingerprint-embedding framework for Drug-Target binding Affinity prediction(FingerDTA),which uses CNN to extract local patterns and utilize fingerprints to characterize global information.These fingerprints are generated on the basis of the whole sequence of drugs or targets.Furthermore,FingerDTA achieves comparable performance on Davis and KIBA data sets.In the case study of screening potential drugs for the spike protein of the coronavirus disease 2019(COVID-19),7 of the top 10 drugs have been confirmed potential by literature.Ultimately,the docking experiment demonstrates that FingerDTA can find novel drug candidates for targets.All codes are available at http://lanproxy.biodwhu.cn:9099/mszjaas/FingerDTA.git.展开更多
文摘Drug target relationship(DTR)prediction is a rapidly evolving area of research in com-putational drug discovery.Despite recent advances in computational solutions that have overcome the challenges of in vitro and in vivo experiments,most computational methods still focus on binary classification.They ignore the importance of binding affinity,which correctly distinguishes between on-targets and off-targets.In this study,we propose a deep learning model based on the microstruc-ture of compounds and proteins to predict drug-target binding affinity(DTA),which utilizes topo-logical structure information of drug molecules and sequence semantic information of proteins.In this model,graph attention network(GAT)is used to capture the deep features of the compound molecular graph,and bidirectional long short-term memory(BiLSTM)network is used to extract the protein sequence features,and the pharmacological context of DTA is obtained by combining the two.The results show that the proposed model has achieved superior performance in both cor-rectly predicting the value of interaction strength and correctly discriminating the ranking of bind-ing strength compared to the state-of-the-art baselines.A case study experiment on COVID-19 con-firms that the proposed DTA model can be used as an effective pre-screening tool in drug discovery.
基金Supported by National Science Foundation,No.NSF-CBET 1232988 and ANSYS Inc.(Canonsburg,PA)
文摘Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas:(1) inhaled drug-aerosol delivery into human lung-airways; and(2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well.Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system.
基金fundings from National Key Research and Development Program of China(Nos.2021YFF1200902 and 2020YFA0712402)National Natural Science Foundation of China(Nos.62273194,61873141,61721003 and 62003178).
文摘Background:Computational approaches for accurate prediction of drug interactions,such as drug-drug interactions(DDIs)and drug-target interactions(DTIs),are highly demanded for biochemical researchers.Despite the fact that many methods have been proposed and developed to predict DDIs and DTIs respectively,their success is still limited due to a lack of systematic evaluation of the intrinsic properties embedded in the corresponding chemical structure.Methods:In this paper,we develop DeepDrug,a deep learning framework for overcoming the above limitation by using residual graph convolutional networks(Res-GCNs)and convolutional networks(CNNs)to learn the comprehensive structure-and sequence-based representations of drugs and proteins.Results:DeepDrug outperforms state-of-the-art methods in a series of systematic experiments,including binary-class DDIs,multi-class/multi-label DDIs,binary-class DTIs classification and DTIs regression tasks.Furthermore,we visualize the structural features learned by DeepDrug Res-GCN module,which displays compatible and accordant patterns in chemical properties and drug categories,providing additional evidence to support the strong predictive power of DeepDrug.Ultimately,we apply DeepDrug to perform drug repositioning on the whole DrugBank database to discover the potential drug candidates against SARS-CoV-2,where 7 out of 10 top-ranked drugs are reported to be repurposed to potentially treat coronavirus disease 2019(COVID-19).Conclusions:To sum up,we believe that DeepDrug is an efficient tool in accurate prediction of DDIs and DTIs and provides a promising insight in understanding the underlying mechanism of these biochemical relations.
基金funded by the National Natural Science Foundation of China,grant number 61402220the key program of Scientific Research Fund of Hunan Provincial Education Department,grant number 19A439the Project supported by the Natural Science Foundation of Hunan Province,China,grant number 2020J4525 and grant number 2022J30495.
文摘Predicting interactions between drugs and target proteins has become an essential task in the drug discovery process.Although the method of validation via wet-lab experiments has become available,experimental methods for drug-target interaction(DTI)identification remain either time consuming or heavily dependent on domain expertise.Therefore,various computational models have been proposed to predict possible interactions between drugs and target proteins.However,most prediction methods do not consider the topological structures characteristics of the relationship.In this paper,we propose a relational topologybased heterogeneous network embedding method to predict drug-target interactions,abbreviated as RTHNE_DTI.We first construct a heterogeneous information network based on the interaction between different types of nodes,to enhance the ability of association discovery by fully considering the topology of the network.Then drug and target protein nodes can be represented by the other types of nodes.According to the different topological structure of the relationship between the nodes,we divide the relationship in the heterogeneous network into two categories and model them separately.Extensive experiments on the realworld drug datasets,RTHNE_DTI produces high efficiency and outperforms other state-of-the-art methods.RTHNE_DTI can be further used to predict the interaction between unknown interaction drug-target pairs.
基金funded by the China National Key Research and Development Program(No.2019YFA0904300).
文摘Many efforts have been exerted toward screening potential drugs for targets,and conducting wet experiments remains a laborious and time-consuming approach.Artificial intelligence methods,such as Convolutional Neural Network(CNN),are widely used to facilitate new drug discovery.Owing to the structural limitations of CNN,features extracted from this method are local patterns that lack global information.However,global information extracted from the whole sequence and local patterns extracted from the special domain can influence the drugtarget affinity.A fusion of global information and local patterns can construct neural network calculations closer to actual biological processes.This paper proposes a Fingerprint-embedding framework for Drug-Target binding Affinity prediction(FingerDTA),which uses CNN to extract local patterns and utilize fingerprints to characterize global information.These fingerprints are generated on the basis of the whole sequence of drugs or targets.Furthermore,FingerDTA achieves comparable performance on Davis and KIBA data sets.In the case study of screening potential drugs for the spike protein of the coronavirus disease 2019(COVID-19),7 of the top 10 drugs have been confirmed potential by literature.Ultimately,the docking experiment demonstrates that FingerDTA can find novel drug candidates for targets.All codes are available at http://lanproxy.biodwhu.cn:9099/mszjaas/FingerDTA.git.
