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1.
Vaibhav Jain Ashish Pandey Shikhar Gupta C. Gopi Mohan 《Journal of molecular modeling》2010,16(4):669-676
Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemokine receptor-3 (CCR3) play
a primary role in the recruitment of eosinophils in allergic asthma. Development of novel and potent CCR3 antagonists could
provide a novel mechanism for inhibition of this recruitment process, thereby preventing asthma. With the intention of designing
new ligands with enhanced inhibitor potencies against CCR3, a 3D-QSAR CoMFA study was carried out on 41 4-benzylpiperidinealkylureas
and amide derivatives. The best statistics of the developed CoMFA model were r
2 = 0.960, rcv2 = 0.589 r_{cv}^2 = 0.589 , n = 32 for the training set and rpred2 = 0.619 r_{pred}^2 = 0.619 , n = 9 for the test set. The generated 3D-QSAR contribution maps shed some light on the effects of the substitution pattern
related to CCR3 antagonist activity. 相似文献
2.
3.
Elena Cichero Sara Cesarini Luisa Mosti Paola Fossa 《Journal of molecular modeling》2010,16(9):1481-1498
Novel classes of cannabinoid 2 receptor (CB2) agonists based on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over cannabinoid
1 receptor (CB1). A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity
indices analysis (CoMSIA) was performed, initially on each series of agonists, and subsequently on all compounds together,
in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the
more predictive, showing cross-validated r2 (rcv
2) = 0.680, non cross-validated r2 (rncv
2) = 0.97 and test set r2( rpred2 ) = 0.93 {{\hbox{r}}^2}\left( {{\hbox{r}}_{\rm{pred}}^2} \right) = 0.{93} . The study provides useful suggestions for the design of new analogues with improved affinity. 相似文献
4.
5.
Penghua Li Jiale Peng Yeheng Zhou Yaping Li XingYong Liu 《Journal of receptor and signal transduction research》2018,38(3):213-224
Human Coagulation Factor IXa (FIXa), specifically inhibited at the initiation stage of the blood coagulation cascade, is an excellent target for developing selective and safe anticoagulants. To explore this inhibitory mechanism, 86 FIXa inhibitors were selected to generate pharmacophore models and subsequently SAR models. Both best pharmacophore model and ROC curve were built through the Receptor–Ligand Pharmacophore Generation module. CoMFA model based on molecular docking and PLS factor analysis methods were developed. Model propagations values are q2?=?0.709, r2?=?0.949, and r2pred?=?0.905. The satisfactory q2 value of 0.609, r2 value of 0.962, and r2pred value of 0.819 for CoMSIA indicated that the CoMFA and CoMSIA models are both available to predict the inhibitory activity on FIXa. On the basis of pharmacophore modeling, molecular docking, and 3D-QSAR modeling screening, six molecules are screened as potential FIXa inhibitors. 相似文献
6.
Peter B. Bright 《Bulletin of mathematical biology》1967,29(1):95-121
Starting from the basic flux equation, it is possible to obtain an integral form relating the current componentsI i at an arbitrary pointr 2 to the distribution of mobilities and concentrationsc i, potential forces\(\bar \mu \), and chemical productivityp i without any restrictive assumptions such as constant mobilities, constant field, steady state, or electrical neutrality. The equation is
$$\begin{gathered} I_i (r_2 ) = G_i (r_2 )\left[ {\Delta \bar \mu _i - \int_{r_1 }^{r_2 } {z_i } FA\left( {p_i - dc_i /dt} \right)\left( {\frac{1}{{G_i (r)}}} \right)dr} \right]; \hfill \\ G_i (r) = 1/\int_{r_1 }^r {\frac{{dr}}{{z_i^2 F^2 c_i u_i }}.} \hfill \\ \end{gathered} $$ 相似文献
7.
Priyanka Shah Sumit Kumar Sunita Tiwari Mohammad Imran Siddiqi 《Journal of chemical biology》2012,5(3):91-103
A series of 35 triazolopyrimidine analogues reported as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors were optimized using quantum mechanics methods, and their binding conformations were studied by docking
and 3D quantitative structure–activity relationship studies. Genetic algorithm-based criteria was adopted for selection of
training and test sets while maintaining structural diversity of training and test sets, which is also very crucial for model
development and validation. Both the comparative molecular field analyses (
q\textLOO2 = 0.841 q_{\text{LOO}}^2 = 0.{841} ,
r\textncv2 = 0.99 r_{\text{ncv}}^2 = 0.{99} ) and comparative molecular similarity indices analyses (
q\textLOO2 = 0.757 q_{\text{LOO}}^2 = 0.{757} ,
r\textncv2 = 0.943 r_{\text{ncv}}^2 = 0.{943} ) show excellent correlation and high predictive power. Furthermore, molecular dynamics simulations were performed to explore
the binding mode of the two of the most active compounds of the series, 10 and 14. Harmonization in the two simulation results validate the analysis and therefore applicability of docking parameters based
on crystallographic conformation of compound 14 bound to receptor molecule. This work provides useful information about the inhibition mechanism of this class of molecules
and will assist in the design of more potent inhibitors of PfDHODH. 相似文献
8.
Partha Pratim Roy 《Molecular simulation》2013,39(11):887-905
Pharmacophore mapping, molecular docking and quantitative structure–activity relationship (QSAR) studies were carried out for a structurally diverse set of 48 compounds as CYP2B6 inhibitors. The generated best pharmacophore hypotheses from the three methods of conformer generation (FAST, BEST and conformer algorithm based on energy screening and recursive buildup) indicate the importance of two features, namely, hydrogen bond acceptor [electron-rich centre] and ring aromaticity. The distance between the two centres of the important features for ideal inhibitors varied from 5.82 to 6.03 Å. The chemometric tools used for the QSAR analysis were genetic function approximation (GFA) and genetic partial least squares. The developed QSAR models indicate the importance of an electron-rich centre, size of molecule, impact of branching and ring system and distribution of charges in the molecular surface. The docking study confirms the importance of an electron-rich centre for binding with the iron atom of the cytochrome enzyme. A GFA model with spline option was found to be the best model based on internal validation as well as the r 2 m (overall) criterion (Q 2 = 0.772, r 2 m (overall) = 0.774). According to the external prediction statistics (R 2 pred = 0.876), another GFA-derived model with spline option outperforms the remaining models. 相似文献
9.
10.
Pseudomonas aeruginosa phosphorylcholine phosphatase (PchP) catalyzes the hydrolysis of phosphorylcholine, which is produced by the action of hemolytic
phospholipase C on phosphatidylcholine or sphyngomielin, to generate choline and inorganic phosphate. Among divalent cations,
its activity is dependent on Mg2+ or Zn2+. Mg2+ produced identical activation at pH 5.0 and 7.4, but Zn2+ was an activator at pH 5.0 and became an inhibitor at pH 7.4. At this higher pH, very low concentrations of Zn2+ inhibited enzymatic activity even in the presence of saturating Mg2+ concentrations. Considering experimental and theoretical physicochemical calculations performed by different authors, we
conclude that at pH 5.0, Mg2+ and Zn2+ are hexacoordinated in an octahedral arrangement in the PchP active site. At pH 7.4, Mg2+ conserves the octahedral coordination maintaining enzymatic activity. The inhibition produced by Zn2+ at 7.4 is interpreted as a change from octahedral to tetrahedral coordination geometry which is produced by hydrolysis of
the
[ \textZn 2+ \textL 2 - 1 \textL 20 ( \textH 2 \textO ) 2 ] \left[ {{\text{Zn}}^{ 2+ } {\text{L}}_{ 2}^{ - 1} {\text{L}}_{ 2}^{0} \left( {{\text{H}}_{ 2} {\text{O}}} \right)_{ 2} } \right] complex. 相似文献
11.
Ana Maria Ronco Yareni Gutierrez Nuri Gras Luis Muñoz Gabriela Salazar Miguel N. Llanos 《Biological trace element research》2010,136(3):269-278
The objective of this study was to evaluate whether lead (Pb) and arsenic (As) levels in biological fluids were associated
to the body composition in a group of reproductive-age women. Voluntary childbearing-age women (n = 107) were divided into three groups according to their body mass index (BMI: weight/height2 (kg/m2): low weight (BMI<18.5 kg/m2), normal $ \left( {{\text{BMI}} > 19\kern1.5pt<\kern1.5pt24.9\,{{\text{kg}} \mathord{\left/{\vphantom {{\text{kg}} {{{\text{m}}^{\text{2}}}}}} \right.} {{{\text{m}}^{\text{2}}}}}} \right) $ \left( {{\text{BMI}} > 19\kern1.5pt<\kern1.5pt24.9\,{{\text{kg}} \mathord{\left/{\vphantom {{\text{kg}} {{{\text{m}}^{\text{2}}}}}} \right.} {{{\text{m}}^{\text{2}}}}}} \right) , and overweight (BMI>25 kg/m2). Body composition and fat mass percentage were determined by the isotopic dilution method utilizing deuterated water. Blood
lead concentrations were determined by graphite furnace atomic absorption spectrometry and urinary arsenic (AsU) concentrations
by inductively coupled plasma mass spectrometry. The type and frequency of food consumption and lifestyle-related factors
were also registered. Most women had $ {\text{PbB}}\,{\text{levels}} > 2\kern1.5pt<\kern1.5pt10\,{\mu{{\text{ g}}} \mathord{\left/{\vphantom {\mu{{\text{ g}}} {\text{dL}}}} \right.} {\text{dL}}} $ {\text{PbB}}\,{\text{levels}} > 2\kern1.5pt<\kern1.5pt10\,{\mu{{\text{ g}}} \mathord{\left/{\vphantom {\mu{{\text{ g}}} {\text{dL}}}} \right.} {\text{dL}}} , and only 2.6% had AsU concentrations above 50 μg/L. The levels of these toxic elements were not found to be associated with
the fat mass percentage. 相似文献
12.
Methanobacterium thermoautotrophicum was grown in continuous culture in a fermenter gassed with H2 and CO2 as sole carbon and energy sources, and in a medium which contained either NH4Cl or gaseous N2 as nitrogen source. Growth was possible with N2. Steady states were obtained at various gas flow rates with NH4Cl and with
and the maintenance coefficient varied with the gas input and with the nitrogen source. Growth of Methanococcus thermolithotrophicus in continuous culture in a fermenter gassed with H2, CO2 as nitrogen, carbon and energy sources was also examined.Abbreviations
molecular growth yield (g dry weight of cells per mol of CH4 evolved)
-
growth rate (h-1)
-
D
dilution rate (h-1)
- rate (h-1);
relation of Neijssel and Tempest and of Stouthamer and Bettenhaussen
-
energy 相似文献
13.
P. Padmini S. K. Rakshit K. Krishnaiah A. Baradarajan 《Bioprocess and biosystems engineering》1994,11(1):39-42
The authors have developed a continuous recycle reactor which efficiently performs emulsion type enzymatic reactions. The reactor column is filled with immobilised lipase and the reactions are effected by pumping the pre-prepared oil-water emulsion through the bottom of the reactor. A part of the product was recycled back and this type of recycling greatly improves the productivity of fatty acid compared to continuous once-through reactor without recycling. The recycle reactor could be continuously run for 35 days without decrease in conversions. The performance of the reactor was interpreted by a model and the theoretical conversion was compared with the experimental data.List of Symbols
F
AO
mol/min
feed rate
-
K
M g/l
Michaelis constant
-
R
recycle ratio
-
r
5
mol/(ml · min)
reaction rate
-
S
0 g/l
initial substrate concentration
-
V
max
mol/(ml · min)
maximum reaction velocity
-
V
R l
void volume of the reactor
-
x
s
fractional conversion
- Standard deviation
相似文献
14.
Yan-Ke Jiang 《Journal of molecular modeling》2010,16(7):1239-1249
Three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried out to
explore the binding of 73 inhibitors to dipeptidyl peptidase IV (DPP-IV), and to construct highly predictive 3D-QSAR models
using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The negative
logarithm of IC50 (pIC50) was used as the biological activity in the 3D-QSAR study. The CoMFA model was developed by steric and electrostatic field
methods, and leave-one-out cross-validated partial least squares analysis yielded a cross-validated value (rcv2 {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} ) of 0.759. Three CoMSIA models developed by different combinations of steric, electrostatic, hydrophobic and hydrogen-bond
fields yielded significant rcv2 {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} values of 0.750, 0.708 and 0.694, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified
test set of 18 compounds. All of the test compounds were predicted accurately using these models. The mean and standard deviation
of prediction errors were within 0.33 and 0.26 for all models. Analysis of CoMFA and CoMSIA contour maps helped identify the
structural requirements of inhibitors, with implications for the design of the next generation of DPP-IV inhibitors for the
treatment of type 2 diabetes. 相似文献
15.
Microsomal prostaglandin E2 synthase (mPGES-1) has been identified recently as a novel target for treating pain and inflammation. The aim of this study
is to understand the binding affinities of reported inhibitors for mPGES-1 and further to design potential new mPGES-1 inhibitors.
3D-QSAR-CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) - techniques
were employed on a series of indole derivatives that act as selective mPGES-1 inhibitors. The lowest energy conformer of the
most active compound obtained from systematic conformational search was used as a template for the alignment of 32 compounds.
The models obtained were used to predict the activities of the test set of eight compounds, and the predicted values were
in good agreement with the experimental results. The 3D-QSAR models derived from the training set of 24 compounds were all
statistically significant (CoMFA; q
2 = 0.89, r
2 = 0.95, , and CoMSIA; q
2 = 0.84, r
2 = 0.93, , ). Contour plots generated for the CoMFA and CoMSIA models reveal useful clues for improving the activity of mPGES-1 inhibitors.
In particular, substitutions of an electronegative fluorine atom or a bulky hydrophilic phenoxy group at the meta or para positions of the biphenyl rings might improve inhibitory activity. A plausible binding mode between the ligands and mPGES-1
is also proposed. 相似文献
16.
B. Culik A. J. Woakes D. Adelung R. P. Wilson N. R. Coria H. J. Spairani 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1990,160(1):61-70
Summary The energy requirements of Adélie penguin (Pygoscelis adeliae) chicks were analysed with respect to body mass (W, 0.145–3.35 kg, n=36) and various forms of activity (lying, standing, minor activity, locomotion, walking on a treadmill). Direct respirometry was used to measure O2 consumption (
) and CO2 production. Heart rate (HR, bpm) was recorded from the ECG obtained by both externally attached electrodes and implantable HR-transmitters. The parameters measured were not affected by hand-rearing of the chicks or by implanting transmitters. HR measured in the laboratory and in the field were comparable. Oxygen uptake ranged from
in lying chicks to
at maximal activity, RQ=0.76. Metabolic rate in small wild chicks (0.14–0.38 kg) was not affected by time of day, nor was their feeding frequency in the colony (Dec 20–21). Regressions of HR on
were highly significant (p< 0.0001) in transmitter implanted chicks (n=4), and two relationships are proposed for the pooled data, one for minor activities (
), and one for walking (
). Oxygen consumption, mass of the chick (2–3 kg), and duration of walking (T, s) were related as
, whereas mass-specific O2 consumption was related to walking speed (S, m·s-1) as
.Abbreviations
bpm
beats per minute
-
D
distance walked (m)
-
ECG
electrocardiogram
-
HR
heart rate (bpm)
-
ns
number of steps
-
RQ
respiratory quotient
-
S
walking speed (m·s-1)
-
T
time walked (s)
-
W
body mass (kg) 相似文献
17.
Mammalian metallothioneins (
\textM7\textIIMTs {\text{M}}_7^{\text{IIMTs}} ) show a clustered arrangement of the metal ions and a nonregular protein structure. The solution structures of Cd3-thiolate cluster containing β-domain of mouse β-MT-1 and rat β-MT-2 show high structural similarities, but widely differing
structure dynamics. Molecular dynamics simulations revealed a substantially increased number of
\textNH - \textSg {\text{NH - }}{{\text{S}}^\gamma } hydrogen bonds in β-MT-2, features likely responsible for the increased stability of the Cd3-thiolate cluster and the enfolding protein domain. Alterations in the
\textNH - \textSg {\text{NH - }}{{\text{S}}^\gamma } hydrogen-bonding network may provide a rationale for the differences in dynamic properties encountered in the β-domains of
MT-1, -2, and -3 isoforms, believed to be essential for their different biological function. 相似文献
18.
19.
Total height, diameter, index volume, stem straightness, apical dominance, and survival were assessed at 8 years from seed
in an open-pollinated progeny test of 36 families of European chestnut (Castanea sativa Miller) established at two sites in the Atlantic area of Galicia, Spain. Iterative spatial analysis was applied to eliminate
the effect of the spatial dependence in the original data and to estimate accurately genetic parameters for evaluating the
potential for selection of the measured trees. Spatial analysis was very beneficial for growth traits and survival, but less
so if at all for form traits. Estimated individual heritabilities ranged from moderate to high for growth traits ([^(h)]i2 = 0.29 - 0.42 \widehat{h}_i^2 = 0.29 - 0.42 ) and stem straightness ([^(h)]i2 = 0.24 - 0.42 \widehat{h}_i^2 = 0.{24} - 0.{42} ). High coefficients of additive genetic variance were obtained for volume (
[^(\textC)]\textV\textA = 36.5 - 41.5% \widehat{\text{C}}{{\text{V}}_{\text{A}}} = {36}.{5} - {41}.{5}\% ) and straightness (
[^(\textC)]\textV\textA = 44.26 - 53.84% \widehat{\text{C}}{{\text{V}}_{\text{A}}} = {44}.{26} - {53}.{84}\% ). Phenotypic and estimated genetic correlations between growth traits were very high, and correlations between sites indicated
that there was no important family × site interaction. No adverse correlations between traits were evident. The results indicate
the ample potential for selection in the current progeny trial, where responses to within-family and combined selection for
growth traits may be high. Accordingly, three selection scenarios were addressed with the aim to initiate the selection of
individuals for implementing the Forest Breeding Plan of Galicia for European chestnut. 相似文献
20.
ETA subtype selective antagonists constitute a novel and potentially important class of agents for the treatment of pulmonary
hypertension, heart failure, and other pathological conditions. In this paper, 60 benzodiazepine derivatives displaying potent
activities against ETA and ETB subtypes of endothelin receptor were selected to establish the 3D-QSAR models using CoMFA and CoMSIA approaches. These models
show excellent internal predictability and consistency, external validation using test-set 19 compounds yields a good predictive
power for antagonistic potency. Statistical parameters of models were obtained with CoMFA-ETA (q
2 = 0.787, r
2 = 0.935, r
2
pred
= 0.901), CoMFA-ETB (q
2 = 0.842, r
2 = 0.984, r
2
pred
= 0.941), CoMSIA-ETA (q
2 = 0.762, r
2 = 0.971, r
2
pred
= 0.958) and CoMSIA-ETB (q
2 = 0.771, r
2 = 0.974, r
2
pred
= 0.953) respectively. Field contour maps (CoMFA and CoMSIA) corresponding to the ETA and ETB subtypes reflects the characteristic similarities and differences between these types. The results of this paper provide
valuable information to facilitate structural modifications of the title compounds to increase the inhibitory potency and
subtype selectivity of endothelin receptor. 相似文献