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1.
2.
A 3D QSAR analysis has been performed on a series of 67 benzodiazepine analogues reported as γ-secretase inhibitors using
molecular field analysis (MFA), with G/PLS to predict steric and electrostatic molecular field interaction for the activity.
The MFA study was carried out using a training set of 54 compounds. The predictive ability of model developed was assessed
using a test set of 13 compounds ( as high as 0.729). The analyzed MFA model has demonstrated a good fit, having r2 value of 0.858 and cross validated coefficient, value as 0.790. The analysis of the best MFA model provided insight into possible modification of the molecules for better
activity.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
3.
The pathway and ab initio direct kinetics of the decomposition 5-aminotetrazole (5-ATZ) to HN3 and NH2CN was investigated. Reactant, products and transition state were optimized with MP2 and B3LYP methods using 6–311G** and
aug-cc-pVDZ basis sets. The intrinsic reaction coordinate curve of the reaction was calculated using the MP2 method with 6–311G**
basis set. The energies were refined using CCSD(T)/6–311G**. Rate constants were evaluated by conventional transition-state
theory (CVT) and canonical variational transition-state theory (TST), with tunneling effect over 300 to 2,500 K. The results
indicated that the tunneling effect and the variational effect are small for the calculated rate constants. The fitted three-parameter
expression calculated using the CVT and TST methods are and , respectively.
Figure The mechanism of the decomposition process of 5-ATZ to HN3 and NH2CN 相似文献
4.
The interaction of solvated electrons with DNA results in various types of DNA lesions. The in vitro and in vivo sensitisation of DNA to -induced damage is achieved by incorporation of the electron-affinity radiosensitiser bromodeoxyuridine (BUdR) in place of
thymidine. However, in DNA duplexes containing single-stranded regions (bulged BUdR-DNA), the type of lesion is different
and the efficiency of damage is enhanced. In particular, DNA interstrand crosslinks (ICL) form at high efficiency in bulged
DNA but are not detectable in completely duplex DNA. Knowledge about the processes and interactions leading to these differences
is obscure. Previously, we addressed the problem by applying molecular modelling and molecular dynamics (MD) simulations to
a system of normal (BUdR·A)-DNA and a hydrated electron, where the excess electron was modelled as a localised eˉ(H2O)6 anionic cluster. The goal of the present study was to apply the same MD simulation to a wobble system, containing a pyrimidine–pyrimidine mismatched base pair, BUdR·T. The results show an overall dynamic pattern similar
to that of the motion around normal DNA. However, the number of configuration states when was particularly close to DNA is different. Moreover, in the (BUdR·T)-wobble DNA system, the electron frequently approaches
the brominated strand, including BUdR, which was not observed with the normal (BUdR·A)-DNA. The structure and exchange of
water at the sites of immobilisation near DNA were also characterised. The structural dynamics of the wobble DNA is prone to more extensive perturbations,
including frequent formation of cross-strand (cs) interatomic contacts. The structural deviations correlated with approaching DNA from the major groove side, with sodium ions trapped deep in the minor groove. Altogether, the obtained results
confirm and/or throw light on dynamic-structure determinants possibly responsible for the enhanced radiation damage of wobble
DNA.
Figure The structure of the tightly bound single water-layer between the DNA and the electron (Site-8, five H2O molecules, bold capped sticks); the rest of the “second” shell waters (lines, in atom type colour) surround the ˉ(H2O)6 cluster (yellow, space fill). Orange dashed lines H-bonds; only one of the five molecules from the single H2O layer mediates a single-step H-bond bridge with N7(A8); the other four present a network of two(three)-step H-bond bridges
between DNA/ partner atoms 相似文献
5.
3D-QSAR studies of Dipeptidyl peptidase IV inhibitors using a docking based alignment 总被引:1,自引:0,他引:1
Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine
from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones
and maintain glucose homeostasis; this makes it an attractive target for the development of drugs for diabetes. This paper
reports 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique. The conformation
of the molecules in the active site was obtained through docking methods. The QSAR models were generated on two training sets
composed of 74 and 25 molecules which included phenylalanine, thiazolidine, and fluorinated pyrrolidine analogs. The 3D-QSAR
models are robust with statistically significant r2, q2, and values. The CoMFA and CoMSIA models were used to design some new inhibitors with several fold higher binding affinity.
Figure The CoMFA contours around molecule D1T155 (a) steric contours - favored (green); disfavored (yellow) (b) electrostatic contours
- electropositive (blue); electronegative (red) 相似文献
6.
Amino azobenzenes are important dyes in the food and textile industry but their application is limited due to their mutagenicity.
Computational modeling techniques were used to help understand the factors responsible for mutagenicity, and several quantitative
structure toxicity relationship (QSTR) models have been derived. HQSTR (hologram QSTR) analyses indicated that different substituents
at sites on both rings contribute to mutagenicity. Fragment parameters such as bond (B) and connectivity(C), as well as donor-acceptor
(DA)-based model provide significant results (q2 = 0.59, r2 = 0.92, ) explaining these harmful effect. HQSTR results indicated that a bulky group at ring “Y” and small group at ring “X” might
help to decrease mutagenicity. 3D-QSTR based on comparative molecular field analyses (CoMFA) and comparative molecular similarity
index analyses (CoMSIA) are also in agreement with HQSTR. The 3D QSTR studies reveal that steric and electrostatic field effects
have a strong relationship with mutagenicity (for CoMFA: q2 = 0.51, r2 = 0.95, and for CoMSIA: q2 = 0.51, r2 = 0.93 and ). In summary, negative groups and steric bulk at ring “Y” and small groups at carbon-3 of ring “X” might be helpful in reducing
the mutagenicity of azo dyes. 相似文献
7.
A novel molecular connectivity index, , based on the adjacency matrix of molecular graphs and novel atomic valence connectivities, , for predicting the molar diamagnetic susceptibilities of organic compounds is proposed. The is defined as: , where and Ei are the atomic valence connectivity and the valence orbital energy of atom i, respectively. A good QSPR model for molar diamagnetic
susceptibilities can be constructed from and using multivariate linear regression (MLR). The correlation coefficient r, standard error, and average absolute deviation
of the MLR model are 0.9918, 5.56 cgs, and 4.26 cgs, respectively, for the 721 organic compounds tested (training set). Cross-validation
using the leave-one-out method demonstrates that the MLR model is highly reliable statistically. Using the MLR model, the
average absolute deviations of the predicted values of molar diamagnetic susceptibility of another 360 organic compounds (test
set) is 4.34 cgs. The results show that the current method is more effective than literature methods for estimating the molar
diamagnetic susceptibility of an organic compound. The MLR method thus provides an acceptable model for the prediction of
molar diamagnetic susceptibilities of organic compounds.
Figure Plot of calculated vs experimental values of molar diamagnetic susceptibilities using the multivariate linear regression (MLR)
model (Eq. 8) 相似文献
8.
The structures and stability of
1–7 dications were calculated at the ab initio MP2/aug-cc-pVTZ level of theory. The dications AlH2+
1 and
2 were characterized to be unstable thermodynamically. However, these and the stable dications,
3–7 have considerable kinetic barriers for deprotonation. Each of the structures 3–7 contains one or more two-electron three-center (2e–3c) bonds. Aluminum atoms of these dications carry most of the positive charges, as indicated by NBO charge calculations.Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday 相似文献
9.
Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT3 receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT3A receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT3 receptor antagonists.
相似文献
10.
Effects of common soil anions and pH on the uptake and accumulation of perchlorate in lettuce 总被引:1,自引:0,他引:1
A mechanistic understanding of perchlorate () entry into plants is important for establishing the human health risk associated with consumption of contaminated produce
and for assessing the effectiveness of phytoremediation. To determine whether common soil anions affect uptake and accumulation in higher plants, a series of competition experiments using lettuce (Lactuca sativa L.) were conducted between (50 nM) and (4–12 mM), (1–10 mM), or Cl− (5–15 mM) in hydroponic solution. The effects of (0–5 mM) and pH (5.5–7.5) on uptake were also examined. Increasing in solution significantly reduced the amount of taken up by green leaf, butter head, and crisphead lettuces. Sulfate and Cl− had no significant effects on uptake in lettuce over the concentrations tested. Increasing pH significantly reduced the amount of taken up by crisphead and green leaf lettuces, whereas increasing significantly reduced uptake in butter head lettuce. The inhibition by across all lettuce genotypes suggests that may share an ion carrier with , and the decrease in uptake with increasing pH or provides macroscopic evidence for cotransport across the plasma membrane. 相似文献
11.
High groundwater nitrate concentrations inhibit eutrophication of sulphate-rich freshwater wetlands 总被引:2,自引:0,他引:2
E.C.H.E.T. Lucassen A.J.P. Smolders A.L. van der Salm J.G.M. Roelofs 《Biogeochemistry》2004,67(2):249-267
During the last 60 years, pollution of the groundwater with
has greatly increased in many parts of Europe, as a consequence of excessive use of manure and synthetic fertilisers. Monitoring of groundwater-fed wetlands indicated that sediments with high
concentrations had the lowest Fe and
concentrations in the pore water. A comparison of two restored open water fens, differing in
supply via the groundwater, indicated that the redox potential and the sulphate (
) reduction rate were lower when the groundwater contained not only
but also high
concentrations. The lower
reduction rates in the
-rich open water fen were associated with lower
concentrations and the presence of plant species characteristic of clear water. In contrast, the higher
reduction rates in the
-poor open water fen were associated with very high
concentrations and massive development of plant species characteristic of eutrophic environments. Investigations at
-rich seepage sites in black alder carrs, showed that high
concentrations in the pore water caused chlorosis in the alder carr vegetation, due to lower availability of Fe in the pore water and less Fe uptake by the plants. Experimental desiccation of sediments proved that the
-rich seepage sites contained no oxidisable FeS
x
, contrary to
-poor locations, which became acidified and mobilised extremely high amounts of
due to FeS
x
oxidation. A laboratory experiment showed that
addition to sediments led to reduced releases of Fe,
and S2–, very likely due to the oxidation of reduced Fe and S compounds. Overall, the results confirmed that
is an energetically more favourable electron acceptor in anaerobic sediments than Fe and
, and that high
loads function as a redox buffer, preventing reduction of Fe and
. Limited
reduction prevents S2– -mediated mobilisation of
from Fe-
complexes. At a higher redox potential, reduced Fe, including FeS
x
, was oxidised, increasing the content of Fe(III) capable of binding
. This prevented increased
availability and the concomitant massive development of plant species characteristic of eutrophic environments. 相似文献
12.
Solvated electrons () are produced during water radiolysis and can interact with biological substrates, including DNA. To augment DNA damage,
radiosensitizers such as bromo-deoxyuridine (BUdR), often referred to as an “electron affinic radiosensitizer”, are incorporated
in place of isosteric thymidine. However, little is known about the primary interactions of with DNA. In the present study we addressed this problem by applying molecular modeling and molecular dynamics (MD) simulations
to a system of normal (BUdR·A)-DNA and a hydrated electron, where the excess electron was modeled as a localized (H2O)6 anionic cluster. Our goals were to evaluate the suitability of the MD simulations for this application; to characterize the
motion of around DNA (e.g., diffusion coefficients); to identify and describe configurational states of close localization to DNA; and to evaluate the structural dynamics of DNA in the presence of . The results indicate that has distinct space-preferences for forming close contacts with DNA and is more likely to interact directly with nucleotides
other than BUdR. Several classes of DNA - contact sites, all within the major groove, were distinguished depending on the structure of the intermediate water layer
H-bonding pattern (or its absence, i.e., a direct H-bonding of with DNA bases). Large-scale structural perturbations were identified during and after the approached the DNA from the major groove side, coupled with deeper penetration of sodium counterions in the minor groove.
Figure A rare configuration showing direct interaction between the solvated electron and DNA, where (yellow) and N7(A16) are H-bonded. The close approach from the major groove side invokes deep Na+ (magenta) penetration into the minor DNA groove (Fig. 7a). 相似文献
13.
Veronique Billat Jean C. Renoux Jacques Pinoteau Bernard Petit Jean P. Koralsztein 《European journal of applied physiology and occupational physiology》1994,69(3):271-273
The aim of this study was to measure running times to exhaustion (Tlim) on a treadmill at 100% of the minimum velocity which elicits
max
max in 38 elite male long - distance runners
max = 71.4 ± 5.5 ml.kg–1.min–1 and
max = 21.8 ± 1.2 km.h–1). The lactate threshold (LT) was defined as a starting point of accelerated lactate accumulation around 4 mM and was expressed in
max. Tlim value was negatively correlated with
max (r = -0.362, p< 0.05) and
max (r = –0.347, p< 0.05) but positively with LT (%v
max) (r = 0.378, p < 0.05). These data demonstrate that running time to exhaustion at
max in a homogeneous group of elite male long-distance runners was inversely related to
max and experimentally illustrates the model of Monod and Scherrer regarding the time limit-velocity relationship adapted from local exercise for running by Hughson et al. (1984) . 相似文献
14.
The tetrameric heart isozyme of lactate dehydrogenase (H4) is modified by p-chloromercuribenzoate (PCMB) to produce the inactive tetramer
and then hybridized with native tetrameric muscle isozyme (M4). The hybrid mixture
was isolated by polyacrylamide gel electrophoresis (PAGE) and then stained for enzyme activity and with Coomassie brilliant blue. Only three bands were found on the gels in either case. The hybrid enzymes
as isolated by PAGE have half the specific activity of the native muscle enzyme. The electrophoresis properties of HM3 are very similar to those of HM3, while the electrophoresis properties of
are very similar to those of H2M2. The above results strongly suggest that the tetramer having enzymatic activity contains at least two native subunits, and the di-subunit in the tetrameric enzyme is the minimal functional unit. 相似文献
15.
Long-term changes in nutrient concentrations of the Changjiang River and principal tributaries 总被引:5,自引:0,他引:5
We present long-term nutrient data on the Changjiang River (Yangtze River) at six hydrological stations and eight principal
tributaries during the period 1958–1985. Three patterns of temporal changes were observed in nitrate
and nitrite : minimal variations in the upper catchment area, rapid increases in the middle watershed towards the end of the 1970s, and
a gradual increase in the lower drainage basin. Prior to the 1970s, the level of throughout the Changjiang River system remained fairly constant. In the 1980s, however, this changed, with the lowest values
in the upper Changjiang changing rapidly to the highest in the middle reaches and then declining slowly but steadily in the
lower courses. Compared to and ammonium and soluble reactive phosphorus (SRP) showed smaller increases or no long-term variations, while dissolved silica (DSi) concentration
generally decreased at most stations. These three patterns of and changes in the Changjiang River system were reflective of the difference in chemical fertilizer use and landscape features
(e.g., slope, soil type and water body area) of the drainage basins of the primary tributaries. The decreases in DSi were
most likely attributed to a reduction in suspended sediment loading due to dam constructions and increasing diatom consumption.
The increase in and with a reduction in DSi concentrations in the Changjiang River could have significant effects on the stoichiometric balance
of nutrients delivered to the East China Sea and the ecosystem in this dynamic region. 相似文献
16.
Regulation of mineral nitrogen uptake in plants 总被引:15,自引:0,他引:15
In the biosphere plants are exposed to different forms of N, which comprise mineral and organic N forms in soils as well as gaseous NH3, NOx, and molecular N2 in the atmosphere. The form of N uptake is mainly determined by its abundance and accessibility, which make
and
the most important N forms for plant nutrition under agricultural conditions. With minor importance, the form of N uptake is also subject to plant preferences, by which plants maintain their cation/anion balance during uptake. However, some species seem to have an obligatory preference which even prevents their growth on certain other N sources. In general, uptake of a certain N form closely matches the growth-related demand of the plant, at least when N transport to the root surface is not limiting. In addition, many plants accumulate large pools of N during vegetative growth which are remobilized in the generative stage. As a consequence, systems responsible for N transport need to be tightly regulated in their expression and activity upon sensing N availability and plant demand. Employing the tools of molecular genetics, the first plant genes encoding transporters for inorganic N have recently been isolated and characterized. These data can now complete the wealth of physiological and nutritional studies on N uptake. The present article will focus on the uptake of
and
into root cells and tries to link data derived from physiological, genetic and molecular studies. 相似文献
17.
Takayoshi Yoshida Junji Kamiya Kouji Hishimoto 《European journal of applied physiology and occupational physiology》1995,70(6):482-486
To assess the rate-limiting factor of oxygen uptake (
) kinetics at the onset of exercise, six healthy male sedentary subjects performed repeated one-legged constant-load cycle exercise. The one-legged constant-load exercise test consisted of two 5-min periods of pedalling at an exercise intensity of 50 W, with a 5-min rest between periods (these exercise periods, i.e. first and second exercises, were performed by the same leg). The exercise was then repeated using the other leg. In addition, two-legged incremental exercise was investigated to establish whether
kinetics were affected by slower heart rate kinetics. The incremental exercise test consisted of two-legged pedalling first with the cycle unloaded as a warm-up for 5 min followed by 50-W exercise for 5 min. The exercise intensity was then increased to 100 W for 5 min. During exercise, gas exchange parameters were determined by the breath-by-breath method and cardiac output (
) was determined continuously by an impedance technique with a computer-based automated system. To determine the kinetics of heart rate (HR),
and
, a best fit procedure was employed using least-squares criteria with a time delay, except during the initial increase. During the one-legged constant-load exercise test,
kinetics were significantly accelerated by repeated exercise using the same leg. On the other hand, when the exercise was changed to the other leg,
kinetics were significantly slower, although
kinetics continued to be faster. During the incremental exercise test, although the HR response was slower at the transition from 50-W to 100-W exercise than at the transition from warm-up to 50-W exercise, there were no significant changes in
kinetics. These findings suggest that
kinetics may be affected by metabolic conditions in the muscle, but not by blood flow (
and/or HR) kinetics. 相似文献
18.
Gill function in an elasmobranch 总被引:1,自引:0,他引:1
Gordon C. Grigg John Read 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》1971,73(4):439-451
Summary Highly efficient oxygen uptake in elasmobranchs, as indicated by frequent excess of
over
has previously been ascribed to the operation of multicapillary rather than counter-current gas exchange by the gills. Analysis of models shows that, at maximum efficiency, a multicapillary system cannot account for values of
greater than
. In Port Jackson sharks Heterodontus portusjacksoni)
commonly exceeds
, which indicates the operation of a functional counter-current at the respiratory surface. The anatomical basis of this counter-current is provided by the demonstration that a continuous flow of water passes between the secondary lamellae into septal canals and thence via the parabranchial cavities to the exterior.Queen Elizabeth II Fellow. 相似文献
19.
Lemaster DM 《Journal of biomolecular NMR》1995,6(4):366-374
Summary The Lipari-Szabo dynamical formalism is extended by setting the time constants of the Lorentzian terms to
and
. This analysis is compared to the earlier proposed three-parameter
extended model free formalism with regard to the range of equivalence and the advantages of the simplified two-parameter (S
inff
sup2
,S
infH
sup2
) and (S
inff
sup2
,S
infN
sup2
) representations. Spectral density components are calculated and compared to those obtained from the spectral density analysis formalism. Protein relaxation data, commonly analyzed in terms of the two-parameter
representation, may correspond to a dynamically heterogeneous behaviour that is more appropriately represented in terms of a fast limit order parameter and a second, lower frequency order parameter. 相似文献
20.
Summary A set of three-dimensional triple-resonance experiments is described which provide
,
,
and
coupling constants. The pulse sequences generate E.COSY-like multiplet patterns and comprise a magnetization transfer from
the amide proton to the α-proton or vice versa via the directly bound heteronuclei. For residues with the 1Hα spin resonating close to the H2O signal, a modified HNCA experiment can be employed to measure the vicinal 1HN,1Hα couplings. Ambiguities associated with the conversion of
values into ϕ-angle constraints for protein structure determination can be resolved with the knowledge of the heteronuclear
3J-couplings. In favourable cases, stereospecific assignments of glycine α-protons can be obtained by employing the experiments
described here in combination with NOE data. The methods are applied to flavodoxin from Desulfovibrio vulgaris. 相似文献