Acetohydroxyacid synthase(AHAS) is the target enzyme of several classes of herbicides,such as sulfonylureas and imidazolinones.Now many mutant AHASs with herbicide resistance have emerged along with extensive use of h...Acetohydroxyacid synthase(AHAS) is the target enzyme of several classes of herbicides,such as sulfonylureas and imidazolinones.Now many mutant AHASs with herbicide resistance have emerged along with extensive use of herbicides,therefore it is imperative to understand the detailed interaction mechanism and resistance mechanism so as to develop new potent inhibitors for wild-type or resistant AHAS.With the aid of available crystal structures of the Arabidopsis thaliana(At) AHAS-inhibitor complex,molecular dynamics(MD) simulations were used to investigate the interaction and resistance mechanism directly and dynamically at the atomic level.Nanosecond-level MD simulations were performed on six systems consisting of wild-type or W574L mutant AtAHAS in the complex with three sulfonylurea inhibitors,separately,and binding free energy was calculated for each system using the MM-GBSA method.Comprehensive analyses from structural and energetic aspects confirmed the importance of residue W574,and also indicated that W574L mutation might alert the structural charactersistic of the substrate access channel and decrease the binding affinity of inhibitors,which cooperatively weaken the effective channel-blocked effect and finally result in weaker inhibitory effect of inhibitor and corresponding herbicide resistance of W574L mutant.To our knowledge,it is the first report about MD simulations study on the AHAS-related system,which will pave the way to study the interactions between herbicides and wild-type or mutant AHAS dynamically,and decipher the resistance mechanism at the atomic level for better designing new potent anti-resistance herbicides.展开更多
In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ i...In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ in structure by a single methyl group,the inhibitory effect of G1(IC50¼264 nmol/L)on AChE was 80 times stronger than that of G2(IC50¼21,210 nmol/L).Enzyme-kinetic analysis,molecular docking and molecular dynamics(MD)simulations were conducted to better understand the molecular basis for this difference.The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE.The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area(MM/GBSA)method were consistent with the experimental data.The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions(ΔEele+ΔGGB)was responsible for the binding affinities of these two inhibitors.Additionally,analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124,Glu292,Val294 and Phe338 of AChE.In conclusion,the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.展开更多
通过分子对接建立了一系列含二氟甲基磷酸基团(DFMP)或二氟甲基硫酸基团(DFMS)的抑制剂与酪氨酸蛋白磷酸酯酶1B(PTP1B)的相互作用模式,并通过1ns的分子动力学模拟和molecular mechanics/generalized Born surface area(MM/GBSA)方法计...通过分子对接建立了一系列含二氟甲基磷酸基团(DFMP)或二氟甲基硫酸基团(DFMS)的抑制剂与酪氨酸蛋白磷酸酯酶1B(PTP1B)的相互作用模式,并通过1ns的分子动力学模拟和molecular mechanics/generalized Born surface area(MM/GBSA)方法计算了其结合自由能.计算获得的结合自由能排序和抑制剂与靶酶间结合能力排序一致;通过基于主方程的自由能计算方法,获得了抑制剂与靶酶残基间相互作用的信息,这些信息显示DFMP/DFMS基团的负电荷中心与PTP1B的221位精氨酸正电荷中心之间的静电相互作用强弱决定了此类抑制剂的活性,进一步的分析还显示位于DFMP/DFMS基团中的氟原子或其他具有适当原子半径的氢键供体原子会增进此类抑制剂与PTP1B活性位点的结合能力.展开更多
Aim:The present in silico study aimed to evaluate the ATP-binding cassette(ABC)transporter inhibition potential of Bulbine frutescens(B.frutescens)phytochemicals.Methods:Several previous studies and databases were use...Aim:The present in silico study aimed to evaluate the ATP-binding cassette(ABC)transporter inhibition potential of Bulbine frutescens(B.frutescens)phytochemicals.Methods:Several previous studies and databases were used to retrieve the ligands and target protein structure.The molecular docking study was performed using the Auto Dock Tools,and the GROMACS package was applied to accomplish molecular dynamics simulation.Results:Utilizing the molecular docking and simulation approach,~25 phytochemicals were screened against the ABC transporter protein.Docking score analysis revealed that B.frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside exhibited strong binding on the ABC transporter protein with a minimum binding score-9.8 kcal/mol in comparison to the standard ABC transporter inhibitor diltiazem(-6.86 kcal/mol).Furthermore,molecular dynamics simulation for 4’-Demethylknipholone 2’-β-D-glucopyranoside showed an acceptable root mean square deviation,radius of gyration,root mean square fluctuation,and hydrogen bond,in addition to other lead compounds.Conclusion:The in-silico study demonstrated that B.frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside possesses anti-drug resistance properties and requires further testing in preclinical settings.展开更多
Seaweeds possess a wide range of bioactive compounds which have been play a vital role in production of novel pharmaceutical and nutraceutical products resources.The present study employed in silico molecular docking ...Seaweeds possess a wide range of bioactive compounds which have been play a vital role in production of novel pharmaceutical and nutraceutical products resources.The present study employed in silico molecular docking to characterize the biomedical potential of brown seaweed Lobophora variegata through antibacterial,antibiofilm,antioxidant and anticancer activities.The antibacterial activity of L.variegata extracts was analyzed against Escherichia coli,Enterococcus faecalis,Staphylococcus aureus,and Pseudomonas aeruginosa strains producing biofilms.The antioxidant activity was assessed using(2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)),superoxide,and hydroxyl radical scavenging assays.Further,the anticancer,antibacterial,and antioxidant activities of the bioactive compounds were evaluated through molecular docking using GLIDE ligand docking module and prime MM-GBSA module in the Schrodinger software.The phytochemical analysis of the methanolic extract of L.variegata found more phycocompounds which was confirmed by FT-IR and GC-MS.The significant level of phenol and flavonoid were expressed in methanolic extract of L.variegata.In addition,the potent antioxidant activity of the methanolic extract was efficiently expressed during the free radical scavenging assays of ABTS,hydroxyl,and superoxide denoted as 34.94,26.64,and 29.86 mg/g,respectively.The antibacterial and biofilm activities of the methanolic extract of L.variegata had significant results.Moreover,the methanolic extract exhibited cytotoxicity against human colon cancer HT-29 cell lines at an inhibitory concentration is 193.65μg/mL.Through the computational analysis,glyceryl monostearate,2-palmitoylglycerol,phthalic acid,2-chloropropyl ethyl ester,phthalic acid,5-methylhex-2-yl ethyl ester,and l-(+)-ascorbic acid 2,6-dihexadecanoate results as top ranked molecules and shown to be a promising compounds,which were evaluated for anticancer,antioxidant,and antibacterial properties against multi-target proteins.Based on the experimental results,L.v展开更多
基金supported by the National Natural Science Foundation of China (Grant Nos.20432010, 20421202, and 90713011)the National Key Project for Basic Research (Grant Nos.2008DFA30770 and 2010CB126102)Key Project of Ministry of Education,China (Grant No.104189) and Institute of Scientific Computing (ISC) of Nankai University
文摘Acetohydroxyacid synthase(AHAS) is the target enzyme of several classes of herbicides,such as sulfonylureas and imidazolinones.Now many mutant AHASs with herbicide resistance have emerged along with extensive use of herbicides,therefore it is imperative to understand the detailed interaction mechanism and resistance mechanism so as to develop new potent inhibitors for wild-type or resistant AHAS.With the aid of available crystal structures of the Arabidopsis thaliana(At) AHAS-inhibitor complex,molecular dynamics(MD) simulations were used to investigate the interaction and resistance mechanism directly and dynamically at the atomic level.Nanosecond-level MD simulations were performed on six systems consisting of wild-type or W574L mutant AtAHAS in the complex with three sulfonylurea inhibitors,separately,and binding free energy was calculated for each system using the MM-GBSA method.Comprehensive analyses from structural and energetic aspects confirmed the importance of residue W574,and also indicated that W574L mutation might alert the structural charactersistic of the substrate access channel and decrease the binding affinity of inhibitors,which cooperatively weaken the effective channel-blocked effect and finally result in weaker inhibitory effect of inhibitor and corresponding herbicide resistance of W574L mutant.To our knowledge,it is the first report about MD simulations study on the AHAS-related system,which will pave the way to study the interactions between herbicides and wild-type or mutant AHAS dynamically,and decipher the resistance mechanism at the atomic level for better designing new potent anti-resistance herbicides.
基金This work was funded in part of the Research Special Fund for Public Welfare Industry of Health(No.200802041)the National Great Science and Technology Projects(2012ZX09301002,2014ZX09507003-002)+1 种基金the International Collaboration Project(2011DFR31240)Institue of Chinese Materia Medica,China Academy of Chinese Medical Sciences&Peking Union Medical College graduate student innovation fund(2013-1007-18).
文摘In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ in structure by a single methyl group,the inhibitory effect of G1(IC50¼264 nmol/L)on AChE was 80 times stronger than that of G2(IC50¼21,210 nmol/L).Enzyme-kinetic analysis,molecular docking and molecular dynamics(MD)simulations were conducted to better understand the molecular basis for this difference.The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE.The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area(MM/GBSA)method were consistent with the experimental data.The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions(ΔEele+ΔGGB)was responsible for the binding affinities of these two inhibitors.Additionally,analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124,Glu292,Val294 and Phe338 of AChE.In conclusion,the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.
文摘通过分子对接建立了一系列含二氟甲基磷酸基团(DFMP)或二氟甲基硫酸基团(DFMS)的抑制剂与酪氨酸蛋白磷酸酯酶1B(PTP1B)的相互作用模式,并通过1ns的分子动力学模拟和molecular mechanics/generalized Born surface area(MM/GBSA)方法计算了其结合自由能.计算获得的结合自由能排序和抑制剂与靶酶间结合能力排序一致;通过基于主方程的自由能计算方法,获得了抑制剂与靶酶残基间相互作用的信息,这些信息显示DFMP/DFMS基团的负电荷中心与PTP1B的221位精氨酸正电荷中心之间的静电相互作用强弱决定了此类抑制剂的活性,进一步的分析还显示位于DFMP/DFMS基团中的氟原子或其他具有适当原子半径的氢键供体原子会增进此类抑制剂与PTP1B活性位点的结合能力.
基金support from the Indian Council of Medical Research(ICMR),India in the form of ICMR Senior Research fellowship.SK acknowledges the University Grants Commission(UGC),India and Department of Science and Technology(DST),India for providing financial support in the form of UGC-BSR Research Start-Up-Grant[No.F.30-372/2017(BSR)]and DST-SERB Grant(EEQ/2016/000350)respectively.SK also acknowledges DST,India for providing the Departmental DST-FIST grant to the Department of Biochemistry,Central University of Punjab,India.AKS and MS acknowledges CSIR and ICMR,India funding agencies respectively for providing financial assistance in the form of a Senior Research Fellowship.KSP acknowledge DBT,India funding agencies for providing financial assistance in the form of Junior Research Fellowship.
文摘Aim:The present in silico study aimed to evaluate the ATP-binding cassette(ABC)transporter inhibition potential of Bulbine frutescens(B.frutescens)phytochemicals.Methods:Several previous studies and databases were used to retrieve the ligands and target protein structure.The molecular docking study was performed using the Auto Dock Tools,and the GROMACS package was applied to accomplish molecular dynamics simulation.Results:Utilizing the molecular docking and simulation approach,~25 phytochemicals were screened against the ABC transporter protein.Docking score analysis revealed that B.frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside exhibited strong binding on the ABC transporter protein with a minimum binding score-9.8 kcal/mol in comparison to the standard ABC transporter inhibitor diltiazem(-6.86 kcal/mol).Furthermore,molecular dynamics simulation for 4’-Demethylknipholone 2’-β-D-glucopyranoside showed an acceptable root mean square deviation,radius of gyration,root mean square fluctuation,and hydrogen bond,in addition to other lead compounds.Conclusion:The in-silico study demonstrated that B.frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside possesses anti-drug resistance properties and requires further testing in preclinical settings.
文摘Seaweeds possess a wide range of bioactive compounds which have been play a vital role in production of novel pharmaceutical and nutraceutical products resources.The present study employed in silico molecular docking to characterize the biomedical potential of brown seaweed Lobophora variegata through antibacterial,antibiofilm,antioxidant and anticancer activities.The antibacterial activity of L.variegata extracts was analyzed against Escherichia coli,Enterococcus faecalis,Staphylococcus aureus,and Pseudomonas aeruginosa strains producing biofilms.The antioxidant activity was assessed using(2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)),superoxide,and hydroxyl radical scavenging assays.Further,the anticancer,antibacterial,and antioxidant activities of the bioactive compounds were evaluated through molecular docking using GLIDE ligand docking module and prime MM-GBSA module in the Schrodinger software.The phytochemical analysis of the methanolic extract of L.variegata found more phycocompounds which was confirmed by FT-IR and GC-MS.The significant level of phenol and flavonoid were expressed in methanolic extract of L.variegata.In addition,the potent antioxidant activity of the methanolic extract was efficiently expressed during the free radical scavenging assays of ABTS,hydroxyl,and superoxide denoted as 34.94,26.64,and 29.86 mg/g,respectively.The antibacterial and biofilm activities of the methanolic extract of L.variegata had significant results.Moreover,the methanolic extract exhibited cytotoxicity against human colon cancer HT-29 cell lines at an inhibitory concentration is 193.65μg/mL.Through the computational analysis,glyceryl monostearate,2-palmitoylglycerol,phthalic acid,2-chloropropyl ethyl ester,phthalic acid,5-methylhex-2-yl ethyl ester,and l-(+)-ascorbic acid 2,6-dihexadecanoate results as top ranked molecules and shown to be a promising compounds,which were evaluated for anticancer,antioxidant,and antibacterial properties against multi-target proteins.Based on the experimental results,L.v
