Accurate identification of compound–protein interactions(CPIs)in silico may deepen our understanding of the underlying mechanisms of drug action and thus remarkably facilitate drug discovery and development.Conventio...Accurate identification of compound–protein interactions(CPIs)in silico may deepen our understanding of the underlying mechanisms of drug action and thus remarkably facilitate drug discovery and development.Conventional similarity-or docking-based computational methods for predicting CPIs rarely exploit latent features from currently available large-scale unlabeled compound and protein data and often limit their usage to relatively small-scale datasets.In the present study,we propose Deep CPI,a novel general and scalable computational framework that combines effective feature embedding(a technique of representation learning)with powerful deep learning methods to accurately predict CPIs at a large scale.Deep CPI automatically learns the implicit yet expressive low-dimensional features of compounds and proteins from a massive amount of unlabeled data.Evaluations of the measured CPIs in large-scale databases,such as Ch EMBL and Binding DB,as well as of the known drug–target interactions from Drug Bank,demonstrated the superior predictive performance of Deep CPI.Furthermore,several interactions among smallmolecule compounds and three G protein-coupled receptor targets(glucagon-like peptide-1 receptor,glucagon receptor,and vasoactive intestinal peptide receptor)predicted using Deep CPI were experimentally validated.The present study suggests that Deep CPI is a useful and powerful tool for drug discovery and repositioning.The source code of Deep CPI can be downloaded from https://github.com/Fangping Wan/Deep CPI.展开更多
The global spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019(COVID-19).In this study,we developed...The global spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019(COVID-19).In this study,we developed an integrative drug repositioning framework,which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph,literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2.Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1(PARP1)inhibitor,CVL218,currently in Phase I clinical trial,may be repurposed to treat COVID-19.Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect.In addition,we showed that CVL218 can interact with the nucleocapsid(N)protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.展开更多
基金the National Natural Science Foundation of China(Grant Nos.61872216 and81630103 to JZ,81872915 to MWW,81573479 and 81773792 to DY)the National Science and Technology Major Project(Grant No.2018ZX09711003-004-002 to LC)+1 种基金the National Science and Technology Major Project Key New Drug Creation and Manufacturing Program of China(Grant Nos.2018ZX09735-001 to MWW,2018ZX09711002-002-005 to DY)Shanghai Science and Technology Development Fund(Grant Nos.15DZ2291600 to MWW,16ZR1407100 to AD).
文摘Accurate identification of compound–protein interactions(CPIs)in silico may deepen our understanding of the underlying mechanisms of drug action and thus remarkably facilitate drug discovery and development.Conventional similarity-or docking-based computational methods for predicting CPIs rarely exploit latent features from currently available large-scale unlabeled compound and protein data and often limit their usage to relatively small-scale datasets.In the present study,we propose Deep CPI,a novel general and scalable computational framework that combines effective feature embedding(a technique of representation learning)with powerful deep learning methods to accurately predict CPIs at a large scale.Deep CPI automatically learns the implicit yet expressive low-dimensional features of compounds and proteins from a massive amount of unlabeled data.Evaluations of the measured CPIs in large-scale databases,such as Ch EMBL and Binding DB,as well as of the known drug–target interactions from Drug Bank,demonstrated the superior predictive performance of Deep CPI.Furthermore,several interactions among smallmolecule compounds and three G protein-coupled receptor targets(glucagon-like peptide-1 receptor,glucagon receptor,and vasoactive intestinal peptide receptor)predicted using Deep CPI were experimentally validated.The present study suggests that Deep CPI is a useful and powerful tool for drug discovery and repositioning.The source code of Deep CPI can be downloaded from https://github.com/Fangping Wan/Deep CPI.
基金This work was supported in part by the National Natural Science Foundation of China(61872216,81630103,31900862,31725014)Jiangsu Provincial Emergency Project on Prevention and Control of COVID-19 Epidemic(BE2020601)+2 种基金the Nation Science and Technology Major Projects for Major New Drugs Innovation and Development(2018ZX09711003-004-002,2019ZX09301010)Pudong New Area Science and Technology Development Foundation(PKX2019-S08)the Turing Al Institute of Nanjing,and the Zhongguancun Haihua Institute for Frontier Information Technology.
文摘The global spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019(COVID-19).In this study,we developed an integrative drug repositioning framework,which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph,literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2.Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1(PARP1)inhibitor,CVL218,currently in Phase I clinical trial,may be repurposed to treat COVID-19.Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect.In addition,we showed that CVL218 can interact with the nucleocapsid(N)protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.
