The outbreak of Coronavirus Disease 2019(COVID-19)has posed a serious threat to global public health,calling for the development of safe and effective prophylactics and therapeutics against infection of its causative ...The outbreak of Coronavirus Disease 2019(COVID-19)has posed a serious threat to global public health,calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),also known as 2019 novel coronavirus(2019-nCoV).The CoV spike(S)protein plays the most important roles in viral attachment,fusion and entry,and serves as a target for development of antibodies,entry inhibitors and vaccines.Here,we identified the receptor-binding domain(RBD)in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2(ACE2)receptors.SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and,hence,attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells,thus inhibiting their infection to host cells.SARS-CoV RBD-specific antibodies could crossreact with SARS-CoV-2 RBD protein,and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2,suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.展开更多
Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play ...Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.展开更多
AIM： To investigate the functional significance of insulin-like growth factor binding protein-5 （IGFBP-5） overexpression in pancreatic cancer （PaC）.METHODS： The effects of IGFBP-5 on cell growth were assessed by...AIM： To investigate the functional significance of insulin-like growth factor binding protein-5 （IGFBP-5） overexpression in pancreatic cancer （PaC）.METHODS： The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen and phosphatidylinositol activated protein kinase 3-kinase （PI3K） inhibitor treatment.RESULTS： After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 （ERK1/2） activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION： These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.展开更多
Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae(MP)pneumonia(MPP).MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MP...Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae(MP)pneumonia(MPP).MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP(SMPP).SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans.Therefore,identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency.In this study,serum samples were collected from patients with general MPP(GMPP)and SMPP to conduct proteomics profiling.The Fc fragment of the IgG-binding protein(FCGBP)was identified as the most promising indicator of SMPP.Biological enrichment analysis indicated uncontrolled inflammation in SMPP.ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP.Furthermore,the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression.Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment.Among them,a mechanistic target of rapamycin kinase(mTOR)inhibitor,which is a macrolide compound and a cell proliferation inhibitor,was the most promising candidate for targeting SMPP.To our knowledge,this study was the first proteomics-based characterization of patients with SMPP and GMPP.展开更多
The incidence and prevalence of hypertension are increasing as a consequence of the obesity epidemic.Adipocytes and their variety of factors make contributions to the long-term regulation of blood pressure.The pathoph...The incidence and prevalence of hypertension are increasing as a consequence of the obesity epidemic.Adipocytes and their variety of factors make contributions to the long-term regulation of blood pressure.The pathophysiologic states of hypertension,including obesity,are regulated by the production of adipocytederived factors.Increased body mass index was closely linked to elevated blood pressure.Mostly the hypertensive subjects were obese as well as overweight.There are numerous adipokines,however,this review article only focuses on the major adipokines including chemerin,visfatin,retinol-binding protein 4,plasminogen activator inhibitor-1,monocyte chemotactic protein-1,omentin-1,lipocalin-2,vaspin,progranulin,complement c1q tumor necrosis factor-related protein,and nesfatin-1 role in the pathogenesis of hypertension.This review article concludes the significant association of major adipokines in the pathogenesis of hypertensives.New research should be focused on other newly reported adipokine roles in hypertensive subjects and the management of these adipokines in hypertensive subjects.The discovery of this information could result in the creation of antihypertensive medications,particularly those that focus on obesity-related hypertension.展开更多
As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of ne...As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of new treatment strategies in the AD brain by noninvasive imaging. Several series of compounds derived from Congo red (CR) and Thioflavin T (ThT) have been evaluated as potential probes for the Aβ imaging. They include a diversity of core structures contributing to their affinities to Aβ. Small-molecule inhibi- tors were known to inhibit the formation of Aβ oligomers and fibrils. This inhibition has to be performed in such a way that these inhibitors bind to Aβ in the binding channel where Aβ-binding probes should sit. Therefore, several of them were used as novel core structures to develop Aβ probes, with their de- rivatives exhibiting good Aβ affinities. This approach will facilitate the design of a variety of candidates for Aβ probe molecules and anti-aggregation-therapeutic drugs. Moreover, the finding of Aβ probes with diverse core structures recognized by binding sites on Aβs will likely provide a promising per- spective for the design of 99mTc-labeled probe-derived molecules.展开更多
Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show rece...Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding poses.Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action studies.Current and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging progress.However,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire process.This part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine residues.Recent studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase activities.Here,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on its concentration,optimal levels of NO in cance展开更多
SARS is a positive-stranded virus featuring the largest viral RNA genomes today. The viral main proteinase(Hydrolase), controlling the activities of SARS virus replication , is an attractive target for therapy. We det...SARS is a positive-stranded virus featuring the largest viral RNA genomes today. The viral main proteinase(Hydrolase), controlling the activities of SARS virus replication , is an attractive target for therapy. We determined crystal structure for transmissible gastroenteritis virus(TGEV) hydrolase, and constructed a homology model for SARS coronavirus proteinase on Silicon Graphics station by Insight Ⅱ molecule simulation software. The structure may reveal remarkable degree of conservation of the substrate binding sites. We design an imaginable peptide precursor for inhibitor, and the base shape of pocket and property of the residues may be used as a basis for designing anti-SARS drugs.展开更多
Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently show...Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently shown that TCDD reduces rapidly the activity of CK2（casein kinase II） both in vivo and in vitro. It is found that TCDD has high molecular similarities to the known inhibitors of CK2 catalytic subunit（CK2a）. This suggests that TCDD could also be an ATP-competitive inhibitor of CK2a. In this work, docking TCDD to CK2 was carried out based on the two structures of CK2a from maize and human, respectively. The binding free energies of the predicted CK2a-TCDD complexes estimated by the molecular mechanics/Poisson-Boltzmann surface area（MM/PBSA） method are from -85.1 kJ/mol to -114.3 kJ/mol for maize and are from -96.1 kJ/mol to -118.2 kJ/mol for human, which are comparable to those estimated for the known inhibitor and also ATP with CK2a. The energetic analysis also reveals that the van der Waals interaction is the dominant contribution to the binding free energy. These results are also useful for designing new drugs for a target of overexpressing CK2 in cancers.展开更多
An investigation is reported on the influence of different components of high performance concrete (HPC) on the initial binding capacities (IBC) of chloride ion. The testing results demonstrate that cement has the lar...An investigation is reported on the influence of different components of high performance concrete (HPC) on the initial binding capacities (IBC) of chloride ion. The testing results demonstrate that cement has the largest IBC, and the relative binding ratio is as high as 30% of total ion amount. Among the mineral admixtures, fly ash has the largest IBC of chloride ion. The IBC of silica fume is about 14.4%, which is smaller than that of fly ash. The IBC of refined ground blast-furnace slag (microslag) is abnormal due to the influence of sulfate ion contained. The addition of superplasticizer and corrosion inhibitor containing calcium nitrite weakens the IBC of mixtures. The fluidity and pore-filling effect of mineral admixtures are studied with paste samples with WIC ratio of 0.3. The influence mechanism of various components in high-performance concrete in IBC is studied further through SEM and Mercury Instrusion Porosimetry tests with paste samples at the age of 3 days.展开更多
Cyanide ion was studied as an inhibitor of Jack bean urease at 300 K in 30 mmol/L tris buffer, pH 7. The inhibition was investigated by isothermal titration calorimetry （ITC）. The extended solvation model was used f...Cyanide ion was studied as an inhibitor of Jack bean urease at 300 K in 30 mmol/L tris buffer, pH 7. The inhibition was investigated by isothermal titration calorimetry （ITC）. The extended solvation model was used for CN^- ＋ JBU interaction over the whole range of CN^- concentrations. The binding parameters recovered from the solvation model were attributed to the cyanide ion interaction. It was found that cyanide ion acted as a non-cooperative inhibitor ofurease, and there is a set of 12 ± 0.12 identical and independent binding sites for CN- ions. The dissociation equilibrium constant is 749.99 umol/L. The molar enthalpy of binding is AH= -13.60 kJ mol^-1.展开更多
Objective： To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 （EHD1 EH domain） with three peptides containing NPF ...Objective： To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 （EHD1 EH domain） with three peptides containing NPF （asparagine-proline-phenylalanine）, DPF （aspartic acid-proline-phenylalanine）, and GPF （glycine-proline-phenylalanine） motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods： Molecular dynamics （MD） simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/ generalized Born surface area （MM/GBSA） method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results： The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the struc- tural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions： van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.展开更多
The family Picornaviridae is one of the largest families of human viral pathogens,causing an extensive range of clinical manifestations from mild fever,common cold to serious paralytic poliomyelitis,COPD,etc.,some of ...The family Picornaviridae is one of the largest families of human viral pathogens,causing an extensive range of clinical manifestations from mild fever,common cold to serious paralytic poliomyelitis,COPD,etc.,some of which can even be life-threatening.Picornaviruses also cause zoonotic epidemics that result in dramatic social and economical losses.Although no efficient antivirus agent for prophylaxis or treatment of picornarivus infections has been officially approved yet,a large number of anti-picornavirus compounds with potent activity have been developed and investigated,through which further information about picornavirus has been revealed as well.Viral mRNA translation,viral mRNA replication and especially the viral capsid are the three main targets of these compounds having been extensively studied.The typical one is the WIN series of compounds that bind to the viral capsid and inhibit rival attachment or uncoating.Herein,a perspective on picornavirus inhibitors and a concrete evolution of WIN compounds will be presented in this paper.展开更多
基金supported by the NIH grants(R01AI137472 and R01AI139092)intramural funds of the New York Blood Center(VIM-NYB616 and CFM-NYB595).
文摘The outbreak of Coronavirus Disease 2019(COVID-19)has posed a serious threat to global public health,calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),also known as 2019 novel coronavirus(2019-nCoV).The CoV spike(S)protein plays the most important roles in viral attachment,fusion and entry,and serves as a target for development of antibodies,entry inhibitors and vaccines.Here,we identified the receptor-binding domain(RBD)in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2(ACE2)receptors.SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and,hence,attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells,thus inhibiting their infection to host cells.SARS-CoV RBD-specific antibodies could crossreact with SARS-CoV-2 RBD protein,and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2,suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
文摘Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.
基金Supported by A grant from the Arkansas Master Tobacco Settlement and Arkansas Biosciences Institute
文摘AIM： To investigate the functional significance of insulin-like growth factor binding protein-5 （IGFBP-5） overexpression in pancreatic cancer （PaC）.METHODS： The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen and phosphatidylinositol activated protein kinase 3-kinase （PI3K） inhibitor treatment.RESULTS： After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 （ERK1/2） activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION： These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.
基金supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2019-12M-003)the National Natural Science Foundation of China(No.81741060)the Beijing Municipal Natural Science Foundation(No,7182051).
文摘Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae(MP)pneumonia(MPP).MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP(SMPP).SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans.Therefore,identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency.In this study,serum samples were collected from patients with general MPP(GMPP)and SMPP to conduct proteomics profiling.The Fc fragment of the IgG-binding protein(FCGBP)was identified as the most promising indicator of SMPP.Biological enrichment analysis indicated uncontrolled inflammation in SMPP.ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP.Furthermore,the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression.Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment.Among them,a mechanistic target of rapamycin kinase(mTOR)inhibitor,which is a macrolide compound and a cell proliferation inhibitor,was the most promising candidate for targeting SMPP.To our knowledge,this study was the first proteomics-based characterization of patients with SMPP and GMPP.
文摘The incidence and prevalence of hypertension are increasing as a consequence of the obesity epidemic.Adipocytes and their variety of factors make contributions to the long-term regulation of blood pressure.The pathophysiologic states of hypertension,including obesity,are regulated by the production of adipocytederived factors.Increased body mass index was closely linked to elevated blood pressure.Mostly the hypertensive subjects were obese as well as overweight.There are numerous adipokines,however,this review article only focuses on the major adipokines including chemerin,visfatin,retinol-binding protein 4,plasminogen activator inhibitor-1,monocyte chemotactic protein-1,omentin-1,lipocalin-2,vaspin,progranulin,complement c1q tumor necrosis factor-related protein,and nesfatin-1 role in the pathogenesis of hypertension.This review article concludes the significant association of major adipokines in the pathogenesis of hypertensives.New research should be focused on other newly reported adipokine roles in hypertensive subjects and the management of these adipokines in hypertensive subjects.The discovery of this information could result in the creation of antihypertensive medications,particularly those that focus on obesity-related hypertension.
基金the National Natural Science Foundation of China (Grant No. 20471011)
文摘As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of new treatment strategies in the AD brain by noninvasive imaging. Several series of compounds derived from Congo red (CR) and Thioflavin T (ThT) have been evaluated as potential probes for the Aβ imaging. They include a diversity of core structures contributing to their affinities to Aβ. Small-molecule inhibi- tors were known to inhibit the formation of Aβ oligomers and fibrils. This inhibition has to be performed in such a way that these inhibitors bind to Aβ in the binding channel where Aβ-binding probes should sit. Therefore, several of them were used as novel core structures to develop Aβ probes, with their de- rivatives exhibiting good Aβ affinities. This approach will facilitate the design of a variety of candidates for Aβ probe molecules and anti-aggregation-therapeutic drugs. Moreover, the finding of Aβ probes with diverse core structures recognized by binding sites on Aβs will likely provide a promising per- spective for the design of 99mTc-labeled probe-derived molecules.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81973173 and 81773571),Jiangsu Province Funds for Excellent Young Scientists(No.BK20170088),the Six Talent Peaks Project(No.YY-023)and the 333 Project of Jiangsu Province.
文摘Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding poses.Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action studies.Current and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging progress.However,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire process.This part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine residues.Recent studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase activities.Here,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on its concentration,optimal levels of NO in cance
文摘SARS is a positive-stranded virus featuring the largest viral RNA genomes today. The viral main proteinase(Hydrolase), controlling the activities of SARS virus replication , is an attractive target for therapy. We determined crystal structure for transmissible gastroenteritis virus(TGEV) hydrolase, and constructed a homology model for SARS coronavirus proteinase on Silicon Graphics station by Insight Ⅱ molecule simulation software. The structure may reveal remarkable degree of conservation of the substrate binding sites. We design an imaginable peptide precursor for inhibitor, and the base shape of pocket and property of the residues may be used as a basis for designing anti-SARS drugs.
基金Supported by the International Science and Technology Cooperation Program of China（No.2010DFA31710）, the National Natural Science Foundation of China（No.10974008）, the Doctoral Fund of Innovation from Beijing University of Technology （China）, and the Project from the Italian Association for Cancer Research（No.IG10412）.
文摘Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently shown that TCDD reduces rapidly the activity of CK2（casein kinase II） both in vivo and in vitro. It is found that TCDD has high molecular similarities to the known inhibitors of CK2 catalytic subunit（CK2a）. This suggests that TCDD could also be an ATP-competitive inhibitor of CK2a. In this work, docking TCDD to CK2 was carried out based on the two structures of CK2a from maize and human, respectively. The binding free energies of the predicted CK2a-TCDD complexes estimated by the molecular mechanics/Poisson-Boltzmann surface area（MM/PBSA） method are from -85.1 kJ/mol to -114.3 kJ/mol for maize and are from -96.1 kJ/mol to -118.2 kJ/mol for human, which are comparable to those estimated for the known inhibitor and also ATP with CK2a. The energetic analysis also reveals that the van der Waals interaction is the dominant contribution to the binding free energy. These results are also useful for designing new drugs for a target of overexpressing CK2 in cancers.
文摘An investigation is reported on the influence of different components of high performance concrete (HPC) on the initial binding capacities (IBC) of chloride ion. The testing results demonstrate that cement has the largest IBC, and the relative binding ratio is as high as 30% of total ion amount. Among the mineral admixtures, fly ash has the largest IBC of chloride ion. The IBC of silica fume is about 14.4%, which is smaller than that of fly ash. The IBC of refined ground blast-furnace slag (microslag) is abnormal due to the influence of sulfate ion contained. The addition of superplasticizer and corrosion inhibitor containing calcium nitrite weakens the IBC of mixtures. The fluidity and pore-filling effect of mineral admixtures are studied with paste samples with WIC ratio of 0.3. The influence mechanism of various components in high-performance concrete in IBC is studied further through SEM and Mercury Instrusion Porosimetry tests with paste samples at the age of 3 days.
文摘Cyanide ion was studied as an inhibitor of Jack bean urease at 300 K in 30 mmol/L tris buffer, pH 7. The inhibition was investigated by isothermal titration calorimetry （ITC）. The extended solvation model was used for CN^- ＋ JBU interaction over the whole range of CN^- concentrations. The binding parameters recovered from the solvation model were attributed to the cyanide ion interaction. It was found that cyanide ion acted as a non-cooperative inhibitor ofurease, and there is a set of 12 ± 0.12 identical and independent binding sites for CN- ions. The dissociation equilibrium constant is 749.99 umol/L. The molar enthalpy of binding is AH= -13.60 kJ mol^-1.
基金supported by the National Natural Science Foundation of China(Nos.11172259 and 31471807)the Special Fund for Agro-scientific Research in the Public Interest(No.201403030),China
文摘Objective： To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 （EHD1 EH domain） with three peptides containing NPF （asparagine-proline-phenylalanine）, DPF （aspartic acid-proline-phenylalanine）, and GPF （glycine-proline-phenylalanine） motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods： Molecular dynamics （MD） simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/ generalized Born surface area （MM/GBSA） method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results： The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the struc- tural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions： van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.
基金National Basic Research Program of China (973Program,Grant No. 2009CB825300)National Science Foundation ofChina (Grant No. 21172006)
文摘The family Picornaviridae is one of the largest families of human viral pathogens,causing an extensive range of clinical manifestations from mild fever,common cold to serious paralytic poliomyelitis,COPD,etc.,some of which can even be life-threatening.Picornaviruses also cause zoonotic epidemics that result in dramatic social and economical losses.Although no efficient antivirus agent for prophylaxis or treatment of picornarivus infections has been officially approved yet,a large number of anti-picornavirus compounds with potent activity have been developed and investigated,through which further information about picornavirus has been revealed as well.Viral mRNA translation,viral mRNA replication and especially the viral capsid are the three main targets of these compounds having been extensively studied.The typical one is the WIN series of compounds that bind to the viral capsid and inhibit rival attachment or uncoating.Herein,a perspective on picornavirus inhibitors and a concrete evolution of WIN compounds will be presented in this paper.
