Natural products(NPs)have long been recognized for their therapeutic potential,especially in cancer treatment,due to an ability to interact with multiple cellular pathways.The identification of molecular targets for N...Natural products(NPs)have long been recognized for their therapeutic potential,especially in cancer treatment,due to an ability to interact with multiple cellular pathways.The identification of molecular targets for NPs is a critical step in understanding anticancer mechanisms,with chemical proteomics emerging as a powerful approach.Both label-based and-free proteomic techniques have been utilized to identify these targets,each with their own advantages and limitations.While label-based methods provide high specificity through chemical tagging,the requirement for labeling can be a limitation,potentially altering NP natural properties.Conversely,label-free techniques allow for the detection of NP-protein interactions without structural modification but may struggle with transient interactions or low-abundance targets.Recent advances in artificial intelligence(AI)have further enhanced the field by improving target prediction and streamlining data analysis.AI-driven models,especially machine learning algorithms,have proven effective in processing complex proteomic data and predicting potential NP-protein interactions.The integration of AI with chemical proteomics accelerates target identification and deepens our understanding of the molecular mechanisms underlying the anticancer effects of NPs.This review explores the application of chemical proteomics and AI in the identification of cancer-related targets for NPs,highlighting current challenges and future directions for clinical translation.展开更多
In order to improve the identification capability of ultra wide-band radar,this paper in-troduces a step-variant multiresolution approach for the time-shift parameter estimation. Subsequently,combining with the approa...In order to improve the identification capability of ultra wide-band radar,this paper in-troduces a step-variant multiresolution approach for the time-shift parameter estimation. Subsequently,combining with the approach,a Geometrical Theory of Diffraction(GTD) model-based time-shift Invariant method to target identification using Matching Pursuits and Likelihood Ratio Test(IMPLRT) is developed. Simulation results using measured scattering signatures of two targets in an ultra wide-band chamber are presented contrasting the performance of the IMPLRT to the Wang's MPLRT technique.展开更多
Natural products(NPs)have historically been a fundamental source for drug discovery.Yet the complex nature of NPs presents substantial challenges in pinpointing bioactive constituents,and corresponding targets.In the ...Natural products(NPs)have historically been a fundamental source for drug discovery.Yet the complex nature of NPs presents substantial challenges in pinpointing bioactive constituents,and corresponding targets.In the present study,an innovative natural product virtual screening-interaction-phenotype(NP-VIP)strategy that integrates virtual screening,chemical proteomics,and metabolomics to identify and validate the bioactive targets of NPs.This approach reduces false positive results and enhances the efficiency of target identification.Salvia miltiorrhiza(SM),a herb with recognized therapeutic potential against ischemic stroke(IS),was used to illustrate the workflow.Utilizing virtual screening,chemical proteomics,and metabolomics,potential therapeutic targets for SM in the IS treatment were identified,totaling 29,100,and 78,respectively.Further analysis via the NP-VIP strategy highlighted five high-confidence targets,including poly[ADP-ribose]polymerase 1(PARP1),signal transducer and activator of transcription 3(STAT3),amyloid precursor protein(APP),glutamate-ammonia ligase(GLUL),and glutamate decarboxylase 67(GAD67).These targets were subsequently validated and found to play critical roles in the neuroprotective effects of SM.The study not only underscores the importance of SM in treating IS but also sets a precedent for NP research,proposing a comprehensive approach that could be adapted for broader pharmacological explorations.展开更多
Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress.Both reversible and irreversible covalent inhibitors are developed for targeting lysin...Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress.Both reversible and irreversible covalent inhibitors are developed for targeting lysine residues.The identification of protein targets and binding sites of these lysine-targeting molecules in the whole proteome is crucial to understand their proteome-wide selectivity.For covalent inhibitors,the pull down-based methods including activity-based protein profiling(ABPP)are commonly used to profile their target proteins.For covalent reversible inhibitors,it is not easy to pull down the potential protein targets as the captured proteins may get off beads because of the reversible manner.Here,we report a pair of isotope-labelled click-free probes to competitively identify the protein targets of lysine-targeting covalent reversible small molecules.This pair of isotopic probes consists of a lysinereactive warhead,a desthiobiotin moiety and isotopicable linker.This integrated probe could eliminate the background proteins induced by the click chemistry during the pull-down process.To demonstrate the feasibility of our newly-developed probes for the protein target identification,we selected the natural product Gossypol in that we proved for the first time that it could modify the lysine residue in a covalent reversible manner.Finally,we confirmed that this pair of integrated probes can be used in a competitive manner to precisely identify the protein target as well as binding sites of Gossypol.Interestingly,pretreatment of Gossypol could stop the antibody from recognizing Gossypol-binding proteins.Together,our isotope-labeled click-free probes could be used for whole-proteome profiling of lysine-targeting covalent reversible small molecules.展开更多
Affinity core-shell magnetic nanoparticles （MNPs） were prepared for identifying the target proteins of drugs in the cell lysate when used in combination with nano-high-performance liquid chromatography tandem mass s...Affinity core-shell magnetic nanoparticles （MNPs） were prepared for identifying the target proteins of drugs in the cell lysate when used in combination with nano-high-performance liquid chromatography tandem mass spectrometry （HPLC-MS/MS）-based shotgun proteomic analysis. A number of new potential targets of cyclosporine A （CsA） could be identified, owing to the high efficacy of the affinity MNPs in drug target identification. To the best of our knowledge, this is the first time to reveal such an abundant target spectrum of CsA.展开更多
Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential to...Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC(proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of i CDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism.The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore,KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation(IP) assay confirmed a direct interaction between KAT6A and i CDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of i CDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.展开更多
Chinese medicine(CM)is an important resource for human life understanding and discovery of drugs.However,due to the unclear pharmacological mechanism caused by unclear target,research and international promotion of ma...Chinese medicine(CM)is an important resource for human life understanding and discovery of drugs.However,due to the unclear pharmacological mechanism caused by unclear target,research and international promotion of many active components have made little progress in the past decades of years.CM is mainly composed of multi-ingredients with multi-targets.The identification of targets of multiple active components and the weight analysis of multiple targets in a specific pathological environment,that is,the determination of the most important target is the main obstacle to the mechanism clarification and thus hinders its internationalization.In this review,the main approach to target identification and network pharmacology were summarized.And BIBm(Bayesian inference modeling),a powerful method for drug target identification and key pathway determination was introduced.We aim to provide a new scientific basis and ideas for the development and international promotion of new drugs based on CM.展开更多
Anti-HIV screening with the MT-4/MTT assay on a focused library of structurally diverse natural products has led to the discovery of a group of steroids with potent activities, which include four new ergostane-type st...Anti-HIV screening with the MT-4/MTT assay on a focused library of structurally diverse natural products has led to the discovery of a group of steroids with potent activities, which include four new ergostane-type steroids, named amotsterols A-D （1-4）, together with two known analogs. Among them, the most potent amotsterol D （4） exhibited anti-HIV activity against wild- type and some clinically relevant multidrug resistant HIV-I strains. Subsequent studies on its target identification through a proteomic approach found that compound 4 might target PKM2, a rate limiting enzyme ofglycolysis, in host cells to restrict HIV replication. The docking model of compound 4 to PKM2 showed that the two hydroxyl groups of 4 form hydrogen bonds with the two parallel Y390 in each subunit of PKM2 separately, and the ring C of 4 is sandwiched between the two parallel aromatic rings ofF26. The identified hit compound may have the potential to be further developed as a novel anti-HIVagent. These results demonstrated that an integrated approach, which combines new chemical structures and phenotypic screening with a proteomic approach, could not only identify novel HIV-1 inhibitors, but also elucidate the unknown targets of compound interactions in antiviral drug discovery.展开更多
1.Introduction Infrared Imaging Missiles(IRIMs)are advanced weapons utilizing infrared technology for target detection and tracking.Their sensors capture thermal signatures and convert them into electronic images,enab...1.Introduction Infrared Imaging Missiles(IRIMs)are advanced weapons utilizing infrared technology for target detection and tracking.Their sensors capture thermal signatures and convert them into electronic images,enabling precise target identification and tracking.To a certain extent,the all-weather adaptability of IRIMs enables their effective operation across diverse environmental conditions,providing high targeting accuracy and cost efficiency.展开更多
In response to the issue of fuzzy matching and association when optical observation data are matched with the orbital elements in a catalog database,this paper proposes a matching and association strategy based on the...In response to the issue of fuzzy matching and association when optical observation data are matched with the orbital elements in a catalog database,this paper proposes a matching and association strategy based on the arcsegment difference method.First,a matching error threshold is set to match the observation data with the known catalog database.Second,the matching results for the same day are sorted on the basis of target identity and observation residuals.Different matching error thresholds and arc-segment dynamic association thresholds are then applied to categorize the observation residuals of the same target across different arc-segments,yielding matching results under various thresholds.Finally,the orbital residual is computed through orbit determination(OD),and the positional error is derived by comparing the OD results with the orbit track from the catalog database.The appropriate matching error threshold is then selected on the basis of these results,leading to the final matching and association of the fuzzy correlation data.Experimental results showed that the correct matching rate for data arc-segments is 92.34% when the matching error threshold is set to 720″,with the arc-segment difference method processing the results of an average matching rate of 97.62% within 8 days.The remaining 5.28% of the fuzzy correlation data are correctly matched and associated,enabling identification of orbital maneuver targets through further processing and analysis.This method substantially enhances the efficiency and accuracy of space target cataloging,offering robust technical support for dynamic maintenance of the space target database.展开更多
[Objectives]To study the network pharmacology-based anticancer effect of Ardisiacrispin B for colon cancer(CRC).[Methods]The chemical structure and molecular properties of Ardisiacrispin B were assessed via the PubChe...[Objectives]To study the network pharmacology-based anticancer effect of Ardisiacrispin B for colon cancer(CRC).[Methods]The chemical structure and molecular properties of Ardisiacrispin B were assessed via the PubChem resource,while the putative target genes of Ardisiacrispin B were predicted using the PharmMapper Database.Moreover,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway and Gene Ontology(GO)enrichment analyses were conducted via the WebGestalt platform.Finally,a drug-target-pathway network was built via Cytoscape to show the visual representation.[Results]Ardisiacrispin B exhibited exceptional druggability with 25 putative targets.Analyses conducted using KEGG,GO,and network methods showed that these target genes were related with inflammatory responses,cancer,and varoius other biological functions.On the basis of these findings,we further screened the correlative biotargets of Ardisiacrispin B in relation to CRC,and explored the anticancer effects of Ardisiacrispin B for the treatment of CRC through CCK8 analysis and colony formation assay.Our results confirmed that Ardisiacrispin B exhibited anti-CRC properties,and suggested 11 candidate targets of Ardisiacrispin B in the treatment of CRC.[Conclusions]Ardisiacrispin B has been demonstrated to target multiple proteins/genes and pathways,thereby forming a network that displays systematic pharmacological activities.Moreover,it has potential therapeutic value in tumor treatment,specifically in promoting the proliferation of CRC cells.展开更多
Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we dev...Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we developed a novel photoaffinity probe of ART to globally capture and identify the antimalarial target proteins of ART through chemical proteomics.The results demonstrated that ART can bind to par-asite proteins by both covalent and non-covalent modification,and these may jointly contribute to the antimalarial effects.Our work enriches the research on the antimalarial targets of ART,and provides a new perspective for further exploring the antimalarial mechanism of ART.展开更多
Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are ...Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug treatment.Among the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural products.The unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and technologies.This review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule drugs.The application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.展开更多
Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identifi...Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identification of a potent DHODH inhibitor by proteomic profiling.Cell-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer cells.Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic acid.Moreover,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid.These results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell growth.Thus,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.展开更多
Objective: To investigate the current status of health literacy regarding children’s vision protection among preschool teachers and to provide a basis for targeted training. Methods: A convenience sampling method was...Objective: To investigate the current status of health literacy regarding children’s vision protection among preschool teachers and to provide a basis for targeted training. Methods: A convenience sampling method was employed to conduct a questionnaire survey among 1,442 preschool teachers in Xiangyang City from April to June 2024. The questionnaire covered five dimensions: knowledge, beliefs, behaviors, skills, and policies. Item response rates were used to identify literacy gaps. Results: The overall vision protection literacy of preschool teachers exhibited characteristics of “strong beliefs but weak knowledge and skills”. The item response rates for each dimension, from highest to lowest, were: beliefs (92.7%), policies (81.9%), behaviors (74.8%), knowledge (67.5%), and skills (58.3%). The core gaps were concentrated in the “knowledge” and “skills” dimensions, with significant deficiencies particularly in the understanding of the concept of “hyperopia reserve” (awareness rate: 27.6%), skills in guiding behaviors for myopia prevention and control (mastery rate: < 50%), and the ability to interpret vision screening results (complete mastery rate: 35.0%). Conclusion: Currently, there are significant structural deficiencies in the health literacy of kindergarten teachers regarding children’s vision protection. In the future, greater emphasis should be placed on practical skills training, particularly in enhancing their practical abilities in areas such as “hyperopia reserve” cognition and interpretation of vision screening results.展开更多
The 2022 Nobel Prize in Chemistry was awarded to American scientists Carolyn Bertozzi,K.Barry Sharpless,and Danish scientist Morten P.Merdahl for their contributions to the development of click chemistry and bioorthog...The 2022 Nobel Prize in Chemistry was awarded to American scientists Carolyn Bertozzi,K.Barry Sharpless,and Danish scientist Morten P.Merdahl for their contributions to the development of click chemistry and bioorthogonal chemistry.展开更多
Glioma is difficult to treat due to the unique tumor microenvironment and bloodebrain barrier.(13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]indolizidine(PF403),a phenanthroindolizidine alkaloid,has been identified ...Glioma is difficult to treat due to the unique tumor microenvironment and bloodebrain barrier.(13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]indolizidine(PF403),a phenanthroindolizidine alkaloid,has been identified as a promising therapeutic agent for the treatment of glioma.However,the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated.Hence,a strategy without chemical modification was applied to identify the target of PF403.In this study,we identified nicotinamide phosphoribosyl transferase(NAMPT)as the target of PF403 by using thermal proteome profiling(TPP).Moreover,microscale thermophoresis(MST),surface plasmon resonance(SPR),and isothermal titration calorimetry(ITC)experiments confirmed that NAMPT exhibits good affinity for PF403.Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT,leading to a decrease in the concentration of nicotinamide adenine dinucleotide(NAD ^(+))in U87 cells.X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of piepi interactions with residue Tyr188 to maintain binding with NAMPT(PDB code 8Y55).After NAMPT was knocked down with lentivirus,PF403 lost or partially lost its antitumor activity at the cellular and animal levels.These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.展开更多
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
Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2A...Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.展开更多
Naturally occurring molecules derived from higher plants, animals, microorganisms and minerals play an important role in the discovery and development of novel therapeutic agents. The identification of molecular targe...Naturally occurring molecules derived from higher plants, animals, microorganisms and minerals play an important role in the discovery and development of novel therapeutic agents. The identification of molecular targets is of interest to elucidate the mode of action of these compounds, and it may be employed to set up target-based assays and allow structure-activity relationship studies to guide medicinal chemistry efforts toward lead optimization. In recent years, plant-derived natural compounds possessing potential anti-tumor activities have been garnering much interest and efforts are underway to identify their molecular targets. Here, we attempt to summarize the discoveries of several natural compounds with activities against hematological malignancies, such as adenanthin, oridonin, gambogic acid and wogonoside, the identification of their targets, and their modes of actions.展开更多
基金supported in part by the Science and Technology Development Fund,Macao SAR(0098/2021/A2 and 0048/2023/AFJ)the Chinese Medicine Guangdong Laboratory(HQCML-C-2024006).
文摘Natural products(NPs)have long been recognized for their therapeutic potential,especially in cancer treatment,due to an ability to interact with multiple cellular pathways.The identification of molecular targets for NPs is a critical step in understanding anticancer mechanisms,with chemical proteomics emerging as a powerful approach.Both label-based and-free proteomic techniques have been utilized to identify these targets,each with their own advantages and limitations.While label-based methods provide high specificity through chemical tagging,the requirement for labeling can be a limitation,potentially altering NP natural properties.Conversely,label-free techniques allow for the detection of NP-protein interactions without structural modification but may struggle with transient interactions or low-abundance targets.Recent advances in artificial intelligence(AI)have further enhanced the field by improving target prediction and streamlining data analysis.AI-driven models,especially machine learning algorithms,have proven effective in processing complex proteomic data and predicting potential NP-protein interactions.The integration of AI with chemical proteomics accelerates target identification and deepens our understanding of the molecular mechanisms underlying the anticancer effects of NPs.This review explores the application of chemical proteomics and AI in the identification of cancer-related targets for NPs,highlighting current challenges and future directions for clinical translation.
文摘In order to improve the identification capability of ultra wide-band radar,this paper in-troduces a step-variant multiresolution approach for the time-shift parameter estimation. Subsequently,combining with the approach,a Geometrical Theory of Diffraction(GTD) model-based time-shift Invariant method to target identification using Matching Pursuits and Likelihood Ratio Test(IMPLRT) is developed. Simulation results using measured scattering signatures of two targets in an ultra wide-band chamber are presented contrasting the performance of the IMPLRT to the Wang's MPLRT technique.
基金supported by the National Natural Science Foundations of China(Grant No.:82204584)Liaoning Provincial Science and Technology Projects,China(Project No.:2021JH1/10400055).
文摘Natural products(NPs)have historically been a fundamental source for drug discovery.Yet the complex nature of NPs presents substantial challenges in pinpointing bioactive constituents,and corresponding targets.In the present study,an innovative natural product virtual screening-interaction-phenotype(NP-VIP)strategy that integrates virtual screening,chemical proteomics,and metabolomics to identify and validate the bioactive targets of NPs.This approach reduces false positive results and enhances the efficiency of target identification.Salvia miltiorrhiza(SM),a herb with recognized therapeutic potential against ischemic stroke(IS),was used to illustrate the workflow.Utilizing virtual screening,chemical proteomics,and metabolomics,potential therapeutic targets for SM in the IS treatment were identified,totaling 29,100,and 78,respectively.Further analysis via the NP-VIP strategy highlighted five high-confidence targets,including poly[ADP-ribose]polymerase 1(PARP1),signal transducer and activator of transcription 3(STAT3),amyloid precursor protein(APP),glutamate-ammonia ligase(GLUL),and glutamate decarboxylase 67(GAD67).These targets were subsequently validated and found to play critical roles in the neuroprotective effects of SM.The study not only underscores the importance of SM in treating IS but also sets a precedent for NP research,proposing a comprehensive approach that could be adapted for broader pharmacological explorations.
基金supported by funding from The National Natural Science Foundation of China(No.22177136)the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2022-I2M-2-002).
文摘Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress.Both reversible and irreversible covalent inhibitors are developed for targeting lysine residues.The identification of protein targets and binding sites of these lysine-targeting molecules in the whole proteome is crucial to understand their proteome-wide selectivity.For covalent inhibitors,the pull down-based methods including activity-based protein profiling(ABPP)are commonly used to profile their target proteins.For covalent reversible inhibitors,it is not easy to pull down the potential protein targets as the captured proteins may get off beads because of the reversible manner.Here,we report a pair of isotope-labelled click-free probes to competitively identify the protein targets of lysine-targeting covalent reversible small molecules.This pair of isotopic probes consists of a lysinereactive warhead,a desthiobiotin moiety and isotopicable linker.This integrated probe could eliminate the background proteins induced by the click chemistry during the pull-down process.To demonstrate the feasibility of our newly-developed probes for the protein target identification,we selected the natural product Gossypol in that we proved for the first time that it could modify the lysine residue in a covalent reversible manner.Finally,we confirmed that this pair of integrated probes can be used in a competitive manner to precisely identify the protein target as well as binding sites of Gossypol.Interestingly,pretreatment of Gossypol could stop the antibody from recognizing Gossypol-binding proteins.Together,our isotope-labeled click-free probes could be used for whole-proteome profiling of lysine-targeting covalent reversible small molecules.
基金the National Natural Science Foundations of China，the National Key Laboratory of Organic Biochemistry Opening Foundations
文摘Affinity core-shell magnetic nanoparticles （MNPs） were prepared for identifying the target proteins of drugs in the cell lysate when used in combination with nano-high-performance liquid chromatography tandem mass spectrometry （HPLC-MS/MS）-based shotgun proteomic analysis. A number of new potential targets of cyclosporine A （CsA） could be identified, owing to the high efficacy of the affinity MNPs in drug target identification. To the best of our knowledge, this is the first time to reveal such an abundant target spectrum of CsA.
基金supported by grants from the National Key R&D Program of China (Nos. 2018YFA0107303 and 2020YFA0908100)the National Natural Science Foundation of China (Nos. 81773600and 82102746)+1 种基金the China Postdoctoral Science Foundation (No.2021M690095)the Fundamental Research Funds for the Central Universities (No. 20720180051)。
文摘Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC(proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of i CDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism.The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore,KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation(IP) assay confirmed a direct interaction between KAT6A and i CDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of i CDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.
基金Supported by the National Nature Science Foundation of China(Nos.81960659,81760264,81960394)Applied Basic Research Key Project of Yunnan(202001AS070024)Yunnan Applied Basic Research Projects-Union foundation Management System(No.2018FE001(-294))。
文摘Chinese medicine(CM)is an important resource for human life understanding and discovery of drugs.However,due to the unclear pharmacological mechanism caused by unclear target,research and international promotion of many active components have made little progress in the past decades of years.CM is mainly composed of multi-ingredients with multi-targets.The identification of targets of multiple active components and the weight analysis of multiple targets in a specific pathological environment,that is,the determination of the most important target is the main obstacle to the mechanism clarification and thus hinders its internationalization.In this review,the main approach to target identification and network pharmacology were summarized.And BIBm(Bayesian inference modeling),a powerful method for drug target identification and key pathway determination was introduced.We aim to provide a new scientific basis and ideas for the development and international promotion of new drugs based on CM.
基金supported by the National Natural Science Foundation of China (21532007, U1302222)the "Personalized Medicines-Molecular Signature-based Drug Discovery and Development"+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020321)the Canadian Institutes for Health Research (CIHR)
文摘Anti-HIV screening with the MT-4/MTT assay on a focused library of structurally diverse natural products has led to the discovery of a group of steroids with potent activities, which include four new ergostane-type steroids, named amotsterols A-D （1-4）, together with two known analogs. Among them, the most potent amotsterol D （4） exhibited anti-HIV activity against wild- type and some clinically relevant multidrug resistant HIV-I strains. Subsequent studies on its target identification through a proteomic approach found that compound 4 might target PKM2, a rate limiting enzyme ofglycolysis, in host cells to restrict HIV replication. The docking model of compound 4 to PKM2 showed that the two hydroxyl groups of 4 form hydrogen bonds with the two parallel Y390 in each subunit of PKM2 separately, and the ring C of 4 is sandwiched between the two parallel aromatic rings ofF26. The identified hit compound may have the potential to be further developed as a novel anti-HIVagent. These results demonstrated that an integrated approach, which combines new chemical structures and phenotypic screening with a proteomic approach, could not only identify novel HIV-1 inhibitors, but also elucidate the unknown targets of compound interactions in antiviral drug discovery.
基金co-supported by the China Postdoctoral Science Foundation(No.2024M754304)the Hunan Provincial Natural Science Foundation of China(No.2025JJ60072)。
文摘1.Introduction Infrared Imaging Missiles(IRIMs)are advanced weapons utilizing infrared technology for target detection and tracking.Their sensors capture thermal signatures and convert them into electronic images,enabling precise target identification and tracking.To a certain extent,the all-weather adaptability of IRIMs enables their effective operation across diverse environmental conditions,providing high targeting accuracy and cost efficiency.
基金supported by National Natural Science Foundation of China(12273080).
文摘In response to the issue of fuzzy matching and association when optical observation data are matched with the orbital elements in a catalog database,this paper proposes a matching and association strategy based on the arcsegment difference method.First,a matching error threshold is set to match the observation data with the known catalog database.Second,the matching results for the same day are sorted on the basis of target identity and observation residuals.Different matching error thresholds and arc-segment dynamic association thresholds are then applied to categorize the observation residuals of the same target across different arc-segments,yielding matching results under various thresholds.Finally,the orbital residual is computed through orbit determination(OD),and the positional error is derived by comparing the OD results with the orbit track from the catalog database.The appropriate matching error threshold is then selected on the basis of these results,leading to the final matching and association of the fuzzy correlation data.Experimental results showed that the correct matching rate for data arc-segments is 92.34% when the matching error threshold is set to 720″,with the arc-segment difference method processing the results of an average matching rate of 97.62% within 8 days.The remaining 5.28% of the fuzzy correlation data are correctly matched and associated,enabling identification of orbital maneuver targets through further processing and analysis.This method substantially enhances the efficiency and accuracy of space target cataloging,offering robust technical support for dynamic maintenance of the space target database.
基金Supported by Medical Scientific Research Foundation of Guangdong Province of China(A2022479)University-Hospital Joint Fund Project of Guangzhou University of Traditional Chinese Medicine(GZYZS2024U08).
文摘[Objectives]To study the network pharmacology-based anticancer effect of Ardisiacrispin B for colon cancer(CRC).[Methods]The chemical structure and molecular properties of Ardisiacrispin B were assessed via the PubChem resource,while the putative target genes of Ardisiacrispin B were predicted using the PharmMapper Database.Moreover,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway and Gene Ontology(GO)enrichment analyses were conducted via the WebGestalt platform.Finally,a drug-target-pathway network was built via Cytoscape to show the visual representation.[Results]Ardisiacrispin B exhibited exceptional druggability with 25 putative targets.Analyses conducted using KEGG,GO,and network methods showed that these target genes were related with inflammatory responses,cancer,and varoius other biological functions.On the basis of these findings,we further screened the correlative biotargets of Ardisiacrispin B in relation to CRC,and explored the anticancer effects of Ardisiacrispin B for the treatment of CRC through CCK8 analysis and colony formation assay.Our results confirmed that Ardisiacrispin B exhibited anti-CRC properties,and suggested 11 candidate targets of Ardisiacrispin B in the treatment of CRC.[Conclusions]Ardisiacrispin B has been demonstrated to target multiple proteins/genes and pathways,thereby forming a network that displays systematic pharmacological activities.Moreover,it has potential therapeutic value in tumor treatment,specifically in promoting the proliferation of CRC cells.
基金supported by grants from the National Key Research and Development Program of China(Nos.2020YFA0908000 and 2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202002)+10 种基金the National Natural Science Foundation of China(Nos.82141001,82274182,82074098 and 82173914)the CACMS Innovation Fund(Nos.CI2021A05101 and CI2021A05104):the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(No.CI2021B014)the Science and Technology Foundation of Shenzhen(No.JCYj20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)Establishment of Sino-Austria"Belt and Road"Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(No.2020YFE0205100)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Nos.ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010 and ZZ15-ND-10)Introduce innovative team projects of Jinan(No.202228029)Shenzhen Governmental Sustainable Development Fund(No.KCXFZ20201221173612034)Shenzhen Key Laboratory of Kidney Diseases(No.ZDSYS201504301616234)Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(No.SZGSPO01).
文摘Present research on the antimalarial mechanisms of artemisinin(ART)is mainly focused on covalent drug binding targets alkylated by free radicals,while non-covalent binding targets have rarely been reported.Here,we developed a novel photoaffinity probe of ART to globally capture and identify the antimalarial target proteins of ART through chemical proteomics.The results demonstrated that ART can bind to par-asite proteins by both covalent and non-covalent modification,and these may jointly contribute to the antimalarial effects.Our work enriches the research on the antimalarial targets of ART,and provides a new perspective for further exploring the antimalarial mechanism of ART.
基金supported by grants from the National Natural Science Foundation of China(No.31870946)the Funding of Double First-rate discipline construction(No.CPU2018GF07)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance(No.DQCP20/21MS01).
文摘Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug treatment.Among the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural products.The unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and technologies.This review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule drugs.The application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.
基金supported by AMED Grants(Nos.JP16cm0106112 and JP16cm0106002)JSPS KAKENHI Grants(Nos.JP17H06412,18H05503,JP19K05744,JP20K05857,JP20H05620,JP21H04720,JP22H04922,and JP22K05363).
文摘Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identification of a potent DHODH inhibitor by proteomic profiling.Cell-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer cells.Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic acid.Moreover,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid.These results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell growth.Thus,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.
基金Nursing Discipline Research Project of the Chinese Medical Association Journal House for 2022-2023(Project No.:CMAPH-NRG 2022007)。
文摘Objective: To investigate the current status of health literacy regarding children’s vision protection among preschool teachers and to provide a basis for targeted training. Methods: A convenience sampling method was employed to conduct a questionnaire survey among 1,442 preschool teachers in Xiangyang City from April to June 2024. The questionnaire covered five dimensions: knowledge, beliefs, behaviors, skills, and policies. Item response rates were used to identify literacy gaps. Results: The overall vision protection literacy of preschool teachers exhibited characteristics of “strong beliefs but weak knowledge and skills”. The item response rates for each dimension, from highest to lowest, were: beliefs (92.7%), policies (81.9%), behaviors (74.8%), knowledge (67.5%), and skills (58.3%). The core gaps were concentrated in the “knowledge” and “skills” dimensions, with significant deficiencies particularly in the understanding of the concept of “hyperopia reserve” (awareness rate: 27.6%), skills in guiding behaviors for myopia prevention and control (mastery rate: < 50%), and the ability to interpret vision screening results (complete mastery rate: 35.0%). Conclusion: Currently, there are significant structural deficiencies in the health literacy of kindergarten teachers regarding children’s vision protection. In the future, greater emphasis should be placed on practical skills training, particularly in enhancing their practical abilities in areas such as “hyperopia reserve” cognition and interpretation of vision screening results.
基金supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region(No.2022D01D38)the National Natural Science Foundation of China(Nos.82173681,21977116,82104004,81973223)+1 种基金the Open Project of State Key Laboratory of Natural Medicines(No.SKLNMZZ202213)the State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(No.SKL-HIDCA-2021-1).
文摘The 2022 Nobel Prize in Chemistry was awarded to American scientists Carolyn Bertozzi,K.Barry Sharpless,and Danish scientist Morten P.Merdahl for their contributions to the development of click chemistry and bioorthogonal chemistry.
基金supported financially by the National Natural Science Foundation of China(No.22337007).
文摘Glioma is difficult to treat due to the unique tumor microenvironment and bloodebrain barrier.(13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]indolizidine(PF403),a phenanthroindolizidine alkaloid,has been identified as a promising therapeutic agent for the treatment of glioma.However,the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated.Hence,a strategy without chemical modification was applied to identify the target of PF403.In this study,we identified nicotinamide phosphoribosyl transferase(NAMPT)as the target of PF403 by using thermal proteome profiling(TPP).Moreover,microscale thermophoresis(MST),surface plasmon resonance(SPR),and isothermal titration calorimetry(ITC)experiments confirmed that NAMPT exhibits good affinity for PF403.Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT,leading to a decrease in the concentration of nicotinamide adenine dinucleotide(NAD ^(+))in U87 cells.X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of piepi interactions with residue Tyr188 to maintain binding with NAMPT(PDB code 8Y55).After NAMPT was knocked down with lentivirus,PF403 lost or partially lost its antitumor activity at the cellular and animal levels.These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.
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the CAMS initiative for innovative medicine(2022-I2M-2-002,China)National Natural Science Foundation of China(32141003)。
文摘Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.
基金supported by National Key Research Program of China(NO2015CB910403)the National Natural Science Foundation(81230048+1 种基金8143006181272451)
文摘Naturally occurring molecules derived from higher plants, animals, microorganisms and minerals play an important role in the discovery and development of novel therapeutic agents. The identification of molecular targets is of interest to elucidate the mode of action of these compounds, and it may be employed to set up target-based assays and allow structure-activity relationship studies to guide medicinal chemistry efforts toward lead optimization. In recent years, plant-derived natural compounds possessing potential anti-tumor activities have been garnering much interest and efforts are underway to identify their molecular targets. Here, we attempt to summarize the discoveries of several natural compounds with activities against hematological malignancies, such as adenanthin, oridonin, gambogic acid and wogonoside, the identification of their targets, and their modes of actions.
