Coal has a highly complex chemical structure,similar to polymers,coal is a macromolecular structure composed of a large number of“similar compounds”,which is called the basic structural unit.Understanding coal struc...Coal has a highly complex chemical structure,similar to polymers,coal is a macromolecular structure composed of a large number of“similar compounds”,which is called the basic structural unit.Understanding coal structure is the basis of its transformation and utilization.Shendong(SD)coal was analyzed by FTIR,XRD,XPS,and NMR.The results show that SD coal normalized structure formula is C_(100)H_(68.5)O_(35.7)N_(1.2)S_(0.2)and the average number of aromatic rings is 1.98.-CH_(2)-content accounts for about 82%in aliphatic CeH region,and the ratio of ether bond CeO,aromatic ether C-O and C=O is about 2:1:11 in oxygen-containing functional group region.The d_(002),L_(C),L_(a)and N_(C)of S_(D)coal microcrystalline structure parameters are 0.1832 nm,1.4688 nm,2.0852 nm and 9.017,respectively.Aromatic carbon and aliphatic carbon ratios of SD coal are 55.67%and 29.97%,aromatic cluster size and average methylene chain length are 0.224 and 1.817.Based on these structural parameters,molecular model of SD coal was constructed with^(13)C SSNMR experimental spectra as a reference.The model was constructed with an atom composition of C_(214)H_(214)O_(49)N_(2)S.展开更多
In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal...In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal-G2-α-CNP）. We, for the first time, provided kinetic report and detailed inhibitory effects of both compounds on PPA. Lineweaver-Burk plot revealed that the inhibition was a mixed-noncompetitive type, and only one molecule of inhibitor bound to the enzyme or to the enzyme-substrate complex. Kinetic constants calculated from secondary plots were in millimole range. Dissociation constants of enzyme-inhibitor complex （KEI） were 0.9 mM and 3.5 mM, respectively. Moreover, dissociation constants of enzyme-inhibitor-substrate complex （KESI） were 0.04 mM and 0.31 mM, respectively. These data indicated that the inhibition was more inclined to competitive to Gal-G2-α-CNP hydrolysis. Further molecular docking study manifested that hydrogen bonding formed between acarbose and aspartic acid （Asp300）, histidine （His305） and glycine （Gly3-6）, while hydrogen bonding was observed between chelidonine and glutamic acid （Glu233）, lysine （Lys200） and His305. In addition, rutaecarpine had only one hydrogen bond with Lys200. Our data indicated that chelidonine and rutaecarpine were two promising drug candidates, and chelidonine possessed stronger inhibitory effect compared with rutaecarpine.展开更多
Glutathione peroxidase, the first example of selenoproteins identified in mammals, was subjected to force field calculations and molecular dynamics in order to enable a clearer comprehension of enzymatic selenium cata...Glutathione peroxidase, the first example of selenoproteins identified in mammals, was subjected to force field calculations and molecular dynamics in order to enable a clearer comprehension of enzymatic selenium catalysis. Starting from the established X-ray structure of bovine GPX, all kinetically defined intermediates and enzyme substrate complexes were modelled. The models thus obtained support the hypothesis that the essential steps of the catalysis are three distinct redox changes of the active site selenium which, in the ground state, presents itself at the surface of selenoperoxidases as the center of a characteristic triad built by selenocysteine, glutarnine and tryptophan. In GPX, four arginine residues and a lysine residue provide an electrostatic architecture which, in each reductive step, directs the donor substrate GSH towards the catalytic center in such a way that 1ts sulfhydryl group must react with the selenium moiety. To this end, different equally efficient modes of substrate binding appear possible. The models are consistent with substrate specificity data, kinetic pattern and other functional characteristics of the enzyme. Comparison of molecular models of GPX with those of other members of the GPX superfamily reveals that the cosubstrate binding mechanisrns are unique for the classical type of cytosolic glutathione peroxidases but cannot operate e. g. in plasma GPX and phospholipid hydroperoxide GPX. The structural differences between the selenoperoxidases, shown to be relevant to their specificities, are discussed in terms of functional diversification within the GPX superfamily展开更多
The binding of drugs with human serum albumin（HSA） is a crucial factor influencing the distribution and bioactivity of drugs in the body.To understand the action mechanisms between gallic acid（GA,3,4,5-trihydroxybe...The binding of drugs with human serum albumin（HSA） is a crucial factor influencing the distribution and bioactivity of drugs in the body.To understand the action mechanisms between gallic acid（GA,3,4,5-trihydroxybenzoic acid） and HSA,the binding of GA with HSA was investigated by a combined experimental and computational approach.The fluorescence properties of HSA and the binding parameters of GA collectively indicate that the binding is characterized by static quenching mechanism at one high affinity binding site.According to the estimated molecular distance between the donor（HSA） and the acceptor（GA）,the binding is related to the fluorescence resonance energy transfer.As indicated by the thermodynamic parameters,hydrophobic interaction plays a major role in the GA-HSA complex.Further,the experimental results reveal that GA is bound in the large hydrophobic cavity of subdomain IIA in the site I of HSA,which is well approved by molecular docking.展开更多
The Galerkin method is used to solve the diffusion equation of the distribution function in configurational space for a multibead-rod model,and the dimensionless components of the extra stress tensor are then calculat...The Galerkin method is used to solve the diffusion equation of the distribution function in configurational space for a multibead-rod model,and the dimensionless components of the extra stress tensor are then calculated by means of the expression of ensemble average.The material functions for steady-state shear flow and uniaxial flow and the mechanical properties of rigid-rodlike molecule suspen- sions in superposed flows are obtained numerically.The results indicate that it is promising to employ the mu ltibead-rod models without the constitutive equation in numerical simulations of flows of suspensions.展开更多
Ursolic acid(UA) and oleanolic acid(OA) are insoluble drugs. The objective of this study was to encapsulate them into β-cyclodextrin(β-CD) and compare the solubility and intermolecular force of β-CD with the two is...Ursolic acid(UA) and oleanolic acid(OA) are insoluble drugs. The objective of this study was to encapsulate them into β-cyclodextrin(β-CD) and compare the solubility and intermolecular force of β-CD with the two isomeric triterpenic acids. The host-vip interaction was explored in liquid and solid state by ultraviolet-visible absorption,1H NMR, phase solubility analysis, and differential scanning calorimetry, X-ray powder diffractometry, and molecular modeling studies. Both experimental and theoretical studies revealed that β-CD formed 1: 1 water soluble inclusion complexes and the complexation process was naturally favorable. In addition, the overall results suggested that ring E with a carboxyl group of the drug was encapsulated into the hydrophobic CD nanocavity. Therefore, a clear different inclusion behavior was observed, and UA exhibited better affinity to β-CD compared with OA in various media due to little steric interference, which was beneficial to form stable inclusion complex with β-CD and increase its water solubility effectively.展开更多
The G-quadruplexes formed from G-rich strands in the telomere and oncogene-promoter regions are regarded as new promising targets in the cancer therapy.A G-quadruplex in the downstream flanking region of the signal tr...The G-quadruplexes formed from G-rich strands in the telomere and oncogene-promoter regions are regarded as new promising targets in the cancer therapy.A G-quadruplex in the downstream flanking region of the signal transducer and activator of transcription 3（STAT3） gene was explored.Its folding patterns were proposed to be 3：2：2 and 3：3：1 loop isomers by the mutation analysis by CD spectroscopy.The structures were constructed and refined by molecular modeling method.展开更多
A multibead-rod model is used to replace the constitutive equation of continuum me- chanics in solving flow problems of steady-state planar flows of rigid-rodlike molecular suspensions.The governing equations then con...A multibead-rod model is used to replace the constitutive equation of continuum me- chanics in solving flow problems of steady-state planar flows of rigid-rodlike molecular suspensions.The governing equations then constitute a set of differential equations of the elliptic type,which is more ame- nable to numerical treatment than those of the mixed type.The conservation equations of the flow fields are solved by the boundary element method with linear boundary elements in physical space and the diffusion equation of the distribution function is solved separately by the Galerkin method in phase space. The solution to the flow problem is obtained when the convergence of the iteration procedure between the two spaces has been reached.Several numerical examples are shown and the interesting features of the present method are discussed in this paper.展开更多
Thiosemicarbazones of 2-amino-5-chlorobenzophenone and 3-aminobenzophenone （L1-La） have been synthesized and their Cu（II） complexes （1-4） were afforded via coordination with cupric chloride. All these compounds ...Thiosemicarbazones of 2-amino-5-chlorobenzophenone and 3-aminobenzophenone （L1-La） have been synthesized and their Cu（II） complexes （1-4） were afforded via coordination with cupric chloride. All these compounds were characterized by UV-vis and lR spectroscopy together with CHN elemental analysis. NMR spectroscopy was also applied to characterize the ligands. In vitro cholinesterase inhibitory assays for the complexes （1-4） showed ICso values less than 10 ~molJL, with complex 1 exhibiting the most activity, ICso = 2.15 ~molJL and 2.16 i^molJL for AChE and BuChE, respectively. Molecular modeling simulation revealed the binding interaction template for complex I with the AChE and BuChE receptors. In DPPH assay, the complexes also showed more in vitro antioxidant activities in comt）arison tn their narent li^ands.展开更多
A new series of benzothiazole Schiff bases 3–29 was synthesized and screened for antitumor activity against cervical cancer（Hela） and kidney fibroblast cancer（COS-7） cell lines. Results indicated that compounds 3...A new series of benzothiazole Schiff bases 3–29 was synthesized and screened for antitumor activity against cervical cancer（Hela） and kidney fibroblast cancer（COS-7） cell lines. Results indicated that compounds 3, 14, 19, 27 and 28 have promising activity against Hela cell line with IC50 values of 2.41,3.06, 6.46, 2.22 and 6.25 mmol/L, respectively, in comparison to doxorubicin as a reference antitumor agent（IC50 2.05 mmol/L）. In addition, compound 3 displayed excellent activity against COS-7 cell line with IC50 value of 4.31 mmol/L in comparison to doxorubicin（IC50 3.04 mmol/L）. In the present work,structure based pharmacophore mapping, molecular docking, protein-ligand interaction, fingerprints and binding energy calculations were employed in a virtual screening strategy to identify the interaction between the compounds and the active site of the putative target, EGFR tyrosine kinase. Molecular properties, toxicity, drug-likeness, and drug score profiles of compounds 3, 14, 19, 27, 28 and 29 were also assessed.展开更多
A novel ligand N-4-hydroxyacetophenone isonicotinoyl hydrazone and its manganese(II) and nickel(II) metal complexes have been synthesized. The synthesized Schiff base and its metal complexes have been characterized by...A novel ligand N-4-hydroxyacetophenone isonicotinoyl hydrazone and its manganese(II) and nickel(II) metal complexes have been synthesized. The synthesized Schiff base and its metal complexes have been characterized by physical state determination, melting point and solubility measurements in different solvents, infrared, proton nuclear magnetic resonance, mass spectrometric and powder X-ray spectroscopic techniques. The thermal properties of the prepared compounds were obtained from TG/DTG measurements. On the basis of the analytical techniques, the ligand was found to be bidentate in nature coordinating to the metal ions through the azomethine nitrogen and carbonyl oxygen atoms leading to distorted octahedral geometries of the metal complexes which were modeled using MM2 force field. The ligand and its metal(II) complexes were evaluated for antifungal activity against <i>Aspergillus fumigatus, Aspergillus niger, Candida albicans and Rhizopus stolonifera.</i> The antifungal evaluation results revealed an enhanced activity upon coordination of the ligand with the metal(II) ions. The activity of the metal complex to the tested fungal strains was in the order Ni(II) > Mn(II).展开更多
Theoretical investigation on the structures of the octacoordinated [Nd(CO3)4]5-and the nonacoordinated [Nd(CO3)4.OH2]5-complexes, using the SPARKLE parameters of the lanthanides within MOPAC, revealed that they posses...Theoretical investigation on the structures of the octacoordinated [Nd(CO3)4]5-and the nonacoordinated [Nd(CO3)4.OH2]5-complexes, using the SPARKLE parameters of the lanthanides within MOPAC, revealed that they possessed dodecahedral and square antiprismatic structures respectively with an average Nd-O distance of 0.249 nm. These structures and the Nd-O distances agreed well with those experimentally found in the crystal structures. Replacing the water molecule with a fluoride ion or a mondentatecarbonato ligand resulted in a nonacoordinated distorted square antiprismatic structures where the trans-carbonato groups were twisted. The corresponding decacoordinated structures with two fluoride ions or a bidentatecarbonato group, [Nd(CO3)4·F2]7-and [Nd(CO3)5]7-, were also investigated. In both cases considerable twisting of the transcarbonato groups was observed.展开更多
The inclusion properties of two calix[4]arene derivatives 5,11,17,23 tetra tert butyl 25, 27 bis (isopropyl carbamoyl methoxy) 26,28 diundecenyloxy calix[4]arene (C[4]A) and 25,27 dibutoxy 5,11,17,23 tet...The inclusion properties of two calix[4]arene derivatives 5,11,17,23 tetra tert butyl 25, 27 bis (isopropyl carbamoyl methoxy) 26,28 diundecenyloxy calix[4]arene (C[4]A) and 25,27 dibutoxy 5,11,17,23 tetra tert butyl 26,28 diundecenyloxy calix[4]arene (C[4]B) were studied by gas chromatographic method. It was found that C[4]A could form inclusion complexes with benzene, toluene, methanol and ethanol while C[4]B could only form inclusion complex with methanol, which might be due to the different conformations of C[4]A and C[4]B. Molecular modeling showed that CH/π and OH/π interactions played important roles in the forming of inclusion complexes.展开更多
Recently we constructed a murine IgE phage surfacedisplay library and screened out two IgE (Fab) cloneswith specific binding activity to Trichosanthin (TCS). Inthis work, the Vε and Vκ genes of the two clones werese...Recently we constructed a murine IgE phage surfacedisplay library and screened out two IgE (Fab) cloneswith specific binding activity to Trichosanthin (TCS). Inthis work, the Vε and Vκ genes of the two clones weresequenced and their putative germline gene usages werestudied. On the basis of the known 3D structure of Trichosanthin and antibody, molecular modeling was carriedout to study the antigen-antibody interaction. The possible antigenic determinant sites on the surface of TCSrecognized by both the clones were analyzed, and the reaction forces between TCS and two Fab fragments werealso analyzed respectively.展开更多
Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability.Due to the complex formulation components and preparation process,formulation screening mos...Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability.Due to the complex formulation components and preparation process,formulation screening mostly relies on trial-and-error process with low efficiency.Here liposome formulation prediction models have been built by machine learning(ML)approaches.The important parameters of liposomes,including size,polydispersity index(PDI),zeta potential and encapsulation,are predicted individually by optimal ML algorithm,while the formulation features are also ranked to provide important guidance for formulation design.The analysis of key parameter reveals that drug molecules with logS[-3,-6],molecular complexity[500,1000]and XLogP3(≥2)are priority for preparing liposome with higher encapsulation.In addition,naproxen(NAP)and palmatine HCl(PAL)represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability.The consistency between predicted and experimental value verifies the satisfied accuracy of ML models.As the drug properties are critical for liposome particles,the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations.The modeling structure reveals that NAP molecules could distribute into lipid layer,while most PAL molecules aggregate in the inner aqueous phase of liposome.The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations.In summary,the general prediction models are built to predict liposome formulations,and the impacts of key factors are analyzed by combing ML with molecular modeling.The availability and rationality of these intelligent prediction systems have been proved in this study,which could be applied for liposome formulation development in the future.展开更多
Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in...Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in prophylaxis,calling for the need for drug improvement.Antibodies are drugs preferentially used in infectious diseases and are easy to get from immunized organisms.The current study combined molecular modeling and single memory B cell sequencing to assess candidate sequences before experiments,providing a strategy for the fabrication of SARS-CoV-2 neutralizing antibodies.A total of 128 sequences were obtained after sequencing 196 memory B cells,and 42 sequences were left after merging extremely similar ones and discarding incomplete ones,followed by homology modeling of the antibody variable region.Thirteen candidate sequences were expressed,of which three were tested positive for receptor binding domain recognition but only one was confirmed as having broad neutralization against several SARS-CoV-2 variants.The current study successfully obtained a SARS-CoV-2 antibody with broad neutralizing abilities and provided a strategy for antibody development in emerging infectious diseases using single memory B cell BCR sequencing and computer assistance in antibody fabrication.展开更多
Methylation in the bases of DNA is known to induce B-Z conformation change. In this work, molecular mechanics and normal mode analysis are used to probe how certain methylation affects the internal interactions and th...Methylation in the bases of DNA is known to induce B-Z conformation change. In this work, molecular mechanics and normal mode analysis are used to probe how certain methylation affects the internal interactions and thermodynamic motions in the DNA double helixes in both B and Z conformations, and its implication to B-Z conformation change. By molecular modeling with Insight II, two cases involving cytosine C5 and guanine C8 methylation on both B and Z-form DNA duplex d(CGCGCG)2 are studied in comparison with the corresponding unmethylated duplexes. The internal interaction energies computed based on a molecular mechanics force field and the entropies due to internal motions computed according to a normal mode analysis are in fare agreement with respective observed thermodynamic quantities. The analysis on the computed individual energy terms suggests that the observed B-Z conformation change induced by methylation is primarily driven by enthalpic factors. A combination of changes in Van der Waals interaction, electrostatic interaction and hydrogen bonding likely contributes to the change of enthalpy that favors Z-conformation in the methylated states.展开更多
The antigenic determinants of trichosanthin were predicted by molecular modeling. First, the threedimensional structure model of the antigen-binding fragment of anti-trichosanthin immunoglobulin E was built on the bas...The antigenic determinants of trichosanthin were predicted by molecular modeling. First, the threedimensional structure model of the antigen-binding fragment of anti-trichosanthin immunoglobulin E was built on the basis of its amino-acid sequence and the known three-dimensional structure of an antibody with similar sequence. Secondly, the preferable antigen-antibody interactions were obtained based on the known three-dimensional structure of trichosanthin and of the hypervariable regions of anti-trichosanthin immunoglobulin E. Two regions in the molecular surface of trichosanthin were found to form extensive interactions with the hypervariable regions of the antibody and have been predicted to be the possible antigenic determinants: one is composed of two polypeptide segments, Ile201-Glu210 and Ile225-Asp229, which are close to each other in the three-dimensional structure; and the other is the segment Lys173-Thr178. The former region seems to be the more reasonable antigenic determinant than the latter one.展开更多
In the article a molecular model of oil with nanoparticles on the basis of the model of ideal fluid is considered. It is assumed that the molecular model of the oil can be represented as a homogenous distribution of i...In the article a molecular model of oil with nanoparticles on the basis of the model of ideal fluid is considered. It is assumed that the molecular model of the oil can be represented as a homogenous distribution of identical molecules in space. It is assumed that the central interaction between the oil molecules and nanoparticles, results in a change of the model parameters. It is shown that for an ideal fluid the effect of nanoparticles is reduced to a change of the coefficient at the pressure.展开更多
Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functio...Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functions as an activator of proteins adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)and sirtuin 1(SIRT1).We used molecular modeling to investigate the SIRT1-binding capacity of compound 1 and various structural analogues,such as orirenierine A(2)and orirenierine B(3)isolated from the medicinal plant Oricia renieri.Methods We investigated the binding to human SIRT1(hSIRT1)of 25 natural products including theβ-indoloquinazoline alkaloids 1−3 and analogues,in comparison with the reference product sirtinol(R and S isomers).A sirtinol binding model was elaborated starting from the closed and open state conformations of the catalytic domain of hSIRT1(PDB structures 4KXQ and 4IG9).For each compound bound to SIRT1,the empirical energy of interaction(ΔE)was calculated and compared to that of sirtinol.Results In our model,compound 1 was found to bind modestly to the sirtinol site of SIRT1.In contrast,the presence of a phenolic OH group at position 7 on the quinazolinone moiety conferred a much higher binding capacity.Compound 2 provided SIRT1 protein complexes as stable as those observed with sirtinol.The replacement of the hydroxy substituent(2)with a methoxy group(3)reduced the SIRT1 binding capacity.Other SIRT1-binding natural products were identified,such as the alkaloids orisuaveolines A and B.Structure-binding relationships were discussed.Conclusion The study underlines the capacity of β-indoloquinazoline alkaloids to interact with SIRT1.This deacetylase enzyme could represent a molecular target for the alkaloid 2.This compound merits further attention for the design of drugs active against SIRT1-dependent pathologies.展开更多
基金financed by the Department of education of Gansu Province:Young Doctor Fund Project(2022QB-029)the Fundamental Research Funds for the Central Universities(31920240125-06,31920240059)+1 种基金the Scientific Research Project of Introducing Talents of Northwest Minzu University(xbmuyjrc202215,xbmuyjrc202216)the National Natural Science Foundation of China(22178289).
文摘Coal has a highly complex chemical structure,similar to polymers,coal is a macromolecular structure composed of a large number of“similar compounds”,which is called the basic structural unit.Understanding coal structure is the basis of its transformation and utilization.Shendong(SD)coal was analyzed by FTIR,XRD,XPS,and NMR.The results show that SD coal normalized structure formula is C_(100)H_(68.5)O_(35.7)N_(1.2)S_(0.2)and the average number of aromatic rings is 1.98.-CH_(2)-content accounts for about 82%in aliphatic CeH region,and the ratio of ether bond CeO,aromatic ether C-O and C=O is about 2:1:11 in oxygen-containing functional group region.The d_(002),L_(C),L_(a)and N_(C)of S_(D)coal microcrystalline structure parameters are 0.1832 nm,1.4688 nm,2.0852 nm and 9.017,respectively.Aromatic carbon and aliphatic carbon ratios of SD coal are 55.67%and 29.97%,aromatic cluster size and average methylene chain length are 0.224 and 1.817.Based on these structural parameters,molecular model of SD coal was constructed with^(13)C SSNMR experimental spectra as a reference.The model was constructed with an atom composition of C_(214)H_(214)O_(49)N_(2)S.
基金State Key Laboratory of Natural and Biomimetic Drugs 2013 Funded Project "Establishment and Application an Online Natural Medicines System with Efficient Separation,Structural Identification and Activity Detection"
文摘In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal-G2-α-CNP）. We, for the first time, provided kinetic report and detailed inhibitory effects of both compounds on PPA. Lineweaver-Burk plot revealed that the inhibition was a mixed-noncompetitive type, and only one molecule of inhibitor bound to the enzyme or to the enzyme-substrate complex. Kinetic constants calculated from secondary plots were in millimole range. Dissociation constants of enzyme-inhibitor complex （KEI） were 0.9 mM and 3.5 mM, respectively. Moreover, dissociation constants of enzyme-inhibitor-substrate complex （KESI） were 0.04 mM and 0.31 mM, respectively. These data indicated that the inhibition was more inclined to competitive to Gal-G2-α-CNP hydrolysis. Further molecular docking study manifested that hydrogen bonding formed between acarbose and aspartic acid （Asp300）, histidine （His305） and glycine （Gly3-6）, while hydrogen bonding was observed between chelidonine and glutamic acid （Glu233）, lysine （Lys200） and His305. In addition, rutaecarpine had only one hydrogen bond with Lys200. Our data indicated that chelidonine and rutaecarpine were two promising drug candidates, and chelidonine possessed stronger inhibitory effect compared with rutaecarpine.
文摘Glutathione peroxidase, the first example of selenoproteins identified in mammals, was subjected to force field calculations and molecular dynamics in order to enable a clearer comprehension of enzymatic selenium catalysis. Starting from the established X-ray structure of bovine GPX, all kinetically defined intermediates and enzyme substrate complexes were modelled. The models thus obtained support the hypothesis that the essential steps of the catalysis are three distinct redox changes of the active site selenium which, in the ground state, presents itself at the surface of selenoperoxidases as the center of a characteristic triad built by selenocysteine, glutarnine and tryptophan. In GPX, four arginine residues and a lysine residue provide an electrostatic architecture which, in each reductive step, directs the donor substrate GSH towards the catalytic center in such a way that 1ts sulfhydryl group must react with the selenium moiety. To this end, different equally efficient modes of substrate binding appear possible. The models are consistent with substrate specificity data, kinetic pattern and other functional characteristics of the enzyme. Comparison of molecular models of GPX with those of other members of the GPX superfamily reveals that the cosubstrate binding mechanisrns are unique for the classical type of cytosolic glutathione peroxidases but cannot operate e. g. in plasma GPX and phospholipid hydroperoxide GPX. The structural differences between the selenoperoxidases, shown to be relevant to their specificities, are discussed in terms of functional diversification within the GPX superfamily
基金Supported by the Project of Department of Science and Technology of Jilin Province,China(No.20070424)
文摘The binding of drugs with human serum albumin（HSA） is a crucial factor influencing the distribution and bioactivity of drugs in the body.To understand the action mechanisms between gallic acid（GA,3,4,5-trihydroxybenzoic acid） and HSA,the binding of GA with HSA was investigated by a combined experimental and computational approach.The fluorescence properties of HSA and the binding parameters of GA collectively indicate that the binding is characterized by static quenching mechanism at one high affinity binding site.According to the estimated molecular distance between the donor（HSA） and the acceptor（GA）,the binding is related to the fluorescence resonance energy transfer.As indicated by the thermodynamic parameters,hydrophobic interaction plays a major role in the GA-HSA complex.Further,the experimental results reveal that GA is bound in the large hydrophobic cavity of subdomain IIA in the site I of HSA,which is well approved by molecular docking.
基金The project supported by the National Natural Science Fundation of China.
文摘The Galerkin method is used to solve the diffusion equation of the distribution function in configurational space for a multibead-rod model,and the dimensionless components of the extra stress tensor are then calculated by means of the expression of ensemble average.The material functions for steady-state shear flow and uniaxial flow and the mechanical properties of rigid-rodlike molecule suspen- sions in superposed flows are obtained numerically.The results indicate that it is promising to employ the mu ltibead-rod models without the constitutive equation in numerical simulations of flows of suspensions.
基金supported by grants from the National Natural Science Foundation of China (21303086)the Natural Science Foundation of Jiangsu Province (BK20130884)the Research Fund for Doctoral Program of Higher Education (20123234120012)
文摘Ursolic acid(UA) and oleanolic acid(OA) are insoluble drugs. The objective of this study was to encapsulate them into β-cyclodextrin(β-CD) and compare the solubility and intermolecular force of β-CD with the two isomeric triterpenic acids. The host-vip interaction was explored in liquid and solid state by ultraviolet-visible absorption,1H NMR, phase solubility analysis, and differential scanning calorimetry, X-ray powder diffractometry, and molecular modeling studies. Both experimental and theoretical studies revealed that β-CD formed 1: 1 water soluble inclusion complexes and the complexation process was naturally favorable. In addition, the overall results suggested that ring E with a carboxyl group of the drug was encapsulated into the hydrophobic CD nanocavity. Therefore, a clear different inclusion behavior was observed, and UA exhibited better affinity to β-CD compared with OA in various media due to little steric interference, which was beneficial to form stable inclusion complex with β-CD and increase its water solubility effectively.
基金supported by the National Natural Science Foundation of China(Nos90913004 and 30821001)the Natural Science Foundation of Beijing(No7082101)+1 种基金Program for New Century Excellent Talents in UniversityBeijing Talents Foundation Beijing National Laboratory for Molecular Sciences
文摘The G-quadruplexes formed from G-rich strands in the telomere and oncogene-promoter regions are regarded as new promising targets in the cancer therapy.A G-quadruplex in the downstream flanking region of the signal transducer and activator of transcription 3（STAT3） gene was explored.Its folding patterns were proposed to be 3：2：2 and 3：3：1 loop isomers by the mutation analysis by CD spectroscopy.The structures were constructed and refined by molecular modeling method.
基金The project supported by the National Nature Science Fundation of China.
文摘A multibead-rod model is used to replace the constitutive equation of continuum me- chanics in solving flow problems of steady-state planar flows of rigid-rodlike molecular suspensions.The governing equations then constitute a set of differential equations of the elliptic type,which is more ame- nable to numerical treatment than those of the mixed type.The conservation equations of the flow fields are solved by the boundary element method with linear boundary elements in physical space and the diffusion equation of the distribution function is solved separately by the Galerkin method in phase space. The solution to the flow problem is obtained when the convergence of the iteration procedure between the two spaces has been reached.Several numerical examples are shown and the interesting features of the present method are discussed in this paper.
基金Universiti Sains Malaysia -Science Fund Grant No.1001/PK1M1A/823003 and RU Grant No. 1001/PKIMIA/811196 for the financial support of this work
文摘Thiosemicarbazones of 2-amino-5-chlorobenzophenone and 3-aminobenzophenone （L1-La） have been synthesized and their Cu（II） complexes （1-4） were afforded via coordination with cupric chloride. All these compounds were characterized by UV-vis and lR spectroscopy together with CHN elemental analysis. NMR spectroscopy was also applied to characterize the ligands. In vitro cholinesterase inhibitory assays for the complexes （1-4） showed ICso values less than 10 ~molJL, with complex 1 exhibiting the most activity, ICso = 2.15 ~molJL and 2.16 i^molJL for AChE and BuChE, respectively. Molecular modeling simulation revealed the binding interaction template for complex I with the AChE and BuChE receptors. In DPPH assay, the complexes also showed more in vitro antioxidant activities in comt）arison tn their narent li^ands.
文摘A new series of benzothiazole Schiff bases 3–29 was synthesized and screened for antitumor activity against cervical cancer（Hela） and kidney fibroblast cancer（COS-7） cell lines. Results indicated that compounds 3, 14, 19, 27 and 28 have promising activity against Hela cell line with IC50 values of 2.41,3.06, 6.46, 2.22 and 6.25 mmol/L, respectively, in comparison to doxorubicin as a reference antitumor agent（IC50 2.05 mmol/L）. In addition, compound 3 displayed excellent activity against COS-7 cell line with IC50 value of 4.31 mmol/L in comparison to doxorubicin（IC50 3.04 mmol/L）. In the present work,structure based pharmacophore mapping, molecular docking, protein-ligand interaction, fingerprints and binding energy calculations were employed in a virtual screening strategy to identify the interaction between the compounds and the active site of the putative target, EGFR tyrosine kinase. Molecular properties, toxicity, drug-likeness, and drug score profiles of compounds 3, 14, 19, 27, 28 and 29 were also assessed.
文摘A novel ligand N-4-hydroxyacetophenone isonicotinoyl hydrazone and its manganese(II) and nickel(II) metal complexes have been synthesized. The synthesized Schiff base and its metal complexes have been characterized by physical state determination, melting point and solubility measurements in different solvents, infrared, proton nuclear magnetic resonance, mass spectrometric and powder X-ray spectroscopic techniques. The thermal properties of the prepared compounds were obtained from TG/DTG measurements. On the basis of the analytical techniques, the ligand was found to be bidentate in nature coordinating to the metal ions through the azomethine nitrogen and carbonyl oxygen atoms leading to distorted octahedral geometries of the metal complexes which were modeled using MM2 force field. The ligand and its metal(II) complexes were evaluated for antifungal activity against <i>Aspergillus fumigatus, Aspergillus niger, Candida albicans and Rhizopus stolonifera.</i> The antifungal evaluation results revealed an enhanced activity upon coordination of the ligand with the metal(II) ions. The activity of the metal complex to the tested fungal strains was in the order Ni(II) > Mn(II).
文摘Theoretical investigation on the structures of the octacoordinated [Nd(CO3)4]5-and the nonacoordinated [Nd(CO3)4.OH2]5-complexes, using the SPARKLE parameters of the lanthanides within MOPAC, revealed that they possessed dodecahedral and square antiprismatic structures respectively with an average Nd-O distance of 0.249 nm. These structures and the Nd-O distances agreed well with those experimentally found in the crystal structures. Replacing the water molecule with a fluoride ion or a mondentatecarbonato ligand resulted in a nonacoordinated distorted square antiprismatic structures where the trans-carbonato groups were twisted. The corresponding decacoordinated structures with two fluoride ions or a bidentatecarbonato group, [Nd(CO3)4·F2]7-and [Nd(CO3)5]7-, were also investigated. In both cases considerable twisting of the transcarbonato groups was observed.
文摘The inclusion properties of two calix[4]arene derivatives 5,11,17,23 tetra tert butyl 25, 27 bis (isopropyl carbamoyl methoxy) 26,28 diundecenyloxy calix[4]arene (C[4]A) and 25,27 dibutoxy 5,11,17,23 tetra tert butyl 26,28 diundecenyloxy calix[4]arene (C[4]B) were studied by gas chromatographic method. It was found that C[4]A could form inclusion complexes with benzene, toluene, methanol and ethanol while C[4]B could only form inclusion complex with methanol, which might be due to the different conformations of C[4]A and C[4]B. Molecular modeling showed that CH/π and OH/π interactions played important roles in the forming of inclusion complexes.
文摘Recently we constructed a murine IgE phage surfacedisplay library and screened out two IgE (Fab) cloneswith specific binding activity to Trichosanthin (TCS). Inthis work, the Vε and Vκ genes of the two clones weresequenced and their putative germline gene usages werestudied. On the basis of the known 3D structure of Trichosanthin and antibody, molecular modeling was carriedout to study the antigen-antibody interaction. The possible antigenic determinant sites on the surface of TCSrecognized by both the clones were analyzed, and the reaction forces between TCS and two Fab fragments werealso analyzed respectively.
基金supported by the Multi-Year Research Grants from the University of Macao(MYRG2019-00032-ICMS and MYRG2020-00113-ICMS)the Macao FDCT research grant(0108/2021/A)Molecular modeling was performed at the High-Performance Computing Cluster(HPCC),which is supported by the Information and Communication Technology Office(ICTO)of the University of Macao.
文摘Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability.Due to the complex formulation components and preparation process,formulation screening mostly relies on trial-and-error process with low efficiency.Here liposome formulation prediction models have been built by machine learning(ML)approaches.The important parameters of liposomes,including size,polydispersity index(PDI),zeta potential and encapsulation,are predicted individually by optimal ML algorithm,while the formulation features are also ranked to provide important guidance for formulation design.The analysis of key parameter reveals that drug molecules with logS[-3,-6],molecular complexity[500,1000]and XLogP3(≥2)are priority for preparing liposome with higher encapsulation.In addition,naproxen(NAP)and palmatine HCl(PAL)represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability.The consistency between predicted and experimental value verifies the satisfied accuracy of ML models.As the drug properties are critical for liposome particles,the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations.The modeling structure reveals that NAP molecules could distribute into lipid layer,while most PAL molecules aggregate in the inner aqueous phase of liposome.The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations.In summary,the general prediction models are built to predict liposome formulations,and the impacts of key factors are analyzed by combing ML with molecular modeling.The availability and rationality of these intelligent prediction systems have been proved in this study,which could be applied for liposome formulation development in the future.
基金supported by the Jiangsu Provincial Key Research and Development Program (Grant No.BE2020616)the National Key R&D Program of China (Grant No.2018YFC1200603)+1 种基金the National Science and Technology Major Project (Grant No.2019SWAQ05-5-4)Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University.
文摘Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in prophylaxis,calling for the need for drug improvement.Antibodies are drugs preferentially used in infectious diseases and are easy to get from immunized organisms.The current study combined molecular modeling and single memory B cell sequencing to assess candidate sequences before experiments,providing a strategy for the fabrication of SARS-CoV-2 neutralizing antibodies.A total of 128 sequences were obtained after sequencing 196 memory B cells,and 42 sequences were left after merging extremely similar ones and discarding incomplete ones,followed by homology modeling of the antibody variable region.Thirteen candidate sequences were expressed,of which three were tested positive for receptor binding domain recognition but only one was confirmed as having broad neutralization against several SARS-CoV-2 variants.The current study successfully obtained a SARS-CoV-2 antibody with broad neutralizing abilities and provided a strategy for antibody development in emerging infectious diseases using single memory B cell BCR sequencing and computer assistance in antibody fabrication.
基金the International Joint Research Project of Chongqing University and National University of Singapore (ARF-151-000-014-112) and the Basic and Applied Research Foundation of Chongqing University.
文摘Methylation in the bases of DNA is known to induce B-Z conformation change. In this work, molecular mechanics and normal mode analysis are used to probe how certain methylation affects the internal interactions and thermodynamic motions in the DNA double helixes in both B and Z conformations, and its implication to B-Z conformation change. By molecular modeling with Insight II, two cases involving cytosine C5 and guanine C8 methylation on both B and Z-form DNA duplex d(CGCGCG)2 are studied in comparison with the corresponding unmethylated duplexes. The internal interaction energies computed based on a molecular mechanics force field and the entropies due to internal motions computed according to a normal mode analysis are in fare agreement with respective observed thermodynamic quantities. The analysis on the computed individual energy terms suggests that the observed B-Z conformation change induced by methylation is primarily driven by enthalpic factors. A combination of changes in Van der Waals interaction, electrostatic interaction and hydrogen bonding likely contributes to the change of enthalpy that favors Z-conformation in the methylated states.
文摘The antigenic determinants of trichosanthin were predicted by molecular modeling. First, the threedimensional structure model of the antigen-binding fragment of anti-trichosanthin immunoglobulin E was built on the basis of its amino-acid sequence and the known three-dimensional structure of an antibody with similar sequence. Secondly, the preferable antigen-antibody interactions were obtained based on the known three-dimensional structure of trichosanthin and of the hypervariable regions of anti-trichosanthin immunoglobulin E. Two regions in the molecular surface of trichosanthin were found to form extensive interactions with the hypervariable regions of the antibody and have been predicted to be the possible antigenic determinants: one is composed of two polypeptide segments, Ile201-Glu210 and Ile225-Asp229, which are close to each other in the three-dimensional structure; and the other is the segment Lys173-Thr178. The former region seems to be the more reasonable antigenic determinant than the latter one.
文摘In the article a molecular model of oil with nanoparticles on the basis of the model of ideal fluid is considered. It is assumed that the molecular model of the oil can be represented as a homogenous distribution of identical molecules in space. It is assumed that the central interaction between the oil molecules and nanoparticles, results in a change of the model parameters. It is shown that for an ideal fluid the effect of nanoparticles is reduced to a change of the coefficient at the pressure.
文摘Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functions as an activator of proteins adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)and sirtuin 1(SIRT1).We used molecular modeling to investigate the SIRT1-binding capacity of compound 1 and various structural analogues,such as orirenierine A(2)and orirenierine B(3)isolated from the medicinal plant Oricia renieri.Methods We investigated the binding to human SIRT1(hSIRT1)of 25 natural products including theβ-indoloquinazoline alkaloids 1−3 and analogues,in comparison with the reference product sirtinol(R and S isomers).A sirtinol binding model was elaborated starting from the closed and open state conformations of the catalytic domain of hSIRT1(PDB structures 4KXQ and 4IG9).For each compound bound to SIRT1,the empirical energy of interaction(ΔE)was calculated and compared to that of sirtinol.Results In our model,compound 1 was found to bind modestly to the sirtinol site of SIRT1.In contrast,the presence of a phenolic OH group at position 7 on the quinazolinone moiety conferred a much higher binding capacity.Compound 2 provided SIRT1 protein complexes as stable as those observed with sirtinol.The replacement of the hydroxy substituent(2)with a methoxy group(3)reduced the SIRT1 binding capacity.Other SIRT1-binding natural products were identified,such as the alkaloids orisuaveolines A and B.Structure-binding relationships were discussed.Conclusion The study underlines the capacity of β-indoloquinazoline alkaloids to interact with SIRT1.This deacetylase enzyme could represent a molecular target for the alkaloid 2.This compound merits further attention for the design of drugs active against SIRT1-dependent pathologies.
