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1.
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
2.
Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses using CoMFA and CoMSIA methods were conducted
on a series of fluoropyrrolidine amides as dipeptidyl peptidase IV (DP-IV) inhibitors. The selected ligands were docked into
the binding site of the 3D model of DP-IV using the GOLD software, and the possible interaction models between DP-IV and the
inhibitors were obtained. Based on the binding conformations of these fluoropyrrolidine amides and their alignment inside
the binding pocket of DP-IV, predictive 3D-QSAR models were established by CoMFA and CoMSIA analyses, which had conventional
r
2 and cross-validated coefficient values () up to 0.982 and 0.555 for CoMFA and 0.953 and 0.613 for CoMSIA, respectively. The predictive ability of these models was
validated by six compounds that were in the testing set. Structure-based investigations and the final 3D-QSAR results provide
the guide for designing new potent inhibitors. 相似文献
3.
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
4.
Cichero E Menozzi G Spallarossa A Mosti L Fossa P 《Journal of molecular modeling》2008,14(12):1131-1145
In order to elucidate the structural requirements for human CB1 receptor antagonism, 78 antagonists belonging to five different chemical classes were selected from the literature and docked
into the receptor binding site, built by homology modeling techniques. To further explore the structure-activity relationships
within the considered chemical classes, a pharmacophore model and a QSAR analysis were developed. In a first step five alignments,
one for each group of compounds were generated. All of them were then submitted to a MOE pharmacophore search in order to
obtain a final pharmacophore model representative of the whole dataset which was used to elaborate the following 3D-QSAR analysis,
by means of the CoMFA methodology. The results of these investigations are expected to be useful in the process of design
and development of new potent CB1 antagonists.
Figure Compounds 1-78 are aligned into the putative CB1 receptor binding site. The three key features shared by all of them are reported
in coloured spheres. The hydrophobic/aromatic ones are depicted in purple while the acceptor functions are coloured in blue. 相似文献
5.
6.
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
7.
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
8.
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
9.
Inhibition of leukocyte-specific protein tyrosine kinase (Lck) activity offers one of the approaches for the treatment of
T-cell mediated inflammatory disorders including rheumatoid arthritis, transplant rejection and inflammatory bowel disease.
To explore the relationship between the structures of the N-4 Pyrimidinyl-1H-indazol-4-amines and their Lck inhibition, 3D-QSAR
study using CoMFA analysis have been performed on a dataset of 42 molecules. The bioactive conformation of the template molecule,
selected as the most potent molecule 23 from the series was obtained by performing molecular docking at the ATP binding site of Lck, which is then used to build
the rest of the molecules in the series. The constructed CoMFA model is robust with of 0.603 and conventional r2 of 0.983. The predictive power of the developed model was obtained using a test set of 10 molecules, giving predictive correlation
coefficient of 0.921. CoMFA contour analysis was performed to obtain useful information about the structural requirements
for the Lck inhibitors which could be utilized in its future design.
Figure CoMFA steric contour map. Sterically favored areas (contribution level 80%) are represented by green polyhedra. Sterically
disfavored areas (contribution level 20%) are represented by yellow polyhedra. The active molecule 23 shown in capped sticks.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
10.
A 3D-QSAR analysis has been carried out by comparative molecular field analysis (CoMFA) on a series of distamycin analogs
that bind to the DNA of drug-resistant bacterial strains MRSA, PRSP and VSEF. The structures of the molecules were derived
from the X-ray structure of distamycin bound to DNA and were aligned using the Database alignment method in Sybyl. Statistically significant CoMFA models for each activity were generated. The CoMFA contours throw light on the structure
activity relationship (SAR) and help to identify novel features that can be incorporated into the distamycin framework to
improve the activity. Common contours have been gleaned from the three models to construct a unified model that explains the
steric and electrostatic requirements for antimicrobial activity against the three resistant strains.
Figure A unified CoMFA model for broad-spectrum DNA minor-groove binders 相似文献
11.
3D-QSAR and molecular docking analysis were performed to explore the interaction of estrogen receptors (ERα and ERβ) with
a series of 3-arylquinazolinethione derivatives. Using the conformations of these compounds revealed by molecular docking,
CoMFA analysis resulted in the first quantitative structure-activity relationship (QSAR) and first quantitative structure-selectivity
relationship (QSSR) models predicting the inhibitory activity against ERβ and the selectivity against ERá. The q2 and R2 values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting
both the inhibitory activity and selectivity of 3-arylquinazolinethione derivatives for these protein targets. A set of 3D
contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal modifications of substituents at C2 and C5 of the quinazoline
which my be useful to improve both the activity and selectivity of ERβ/ ERα. Results showed that both the steric and electrostatic
factors should appropriately be taken into account in future rational design and development of more active and more selective
ERβ inhibitors for the therapeutic treatment of osteoporosis.
Figure Structures of ERβ binding with compounds 1aar, 1ax and 1aag obtained from molecular docking 相似文献
12.
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
13.
This work presents new developments of the moving-domain QM/MM (MoD-QM/MM) method for modeling protein electrostatic potentials.
The underlying goal of the method is to map the electronic density of a specific protein configuration into a point-charge
distribution. Important modifications of the general strategy of the MoD-QM/MM method involve new partitioning and fitting
schemes and the incorporation of dynamic effects via a single-step free energy perturbation approach (FEP). Selection of moderately
sized QM domains partitioned between and C (from C=O), with incorporation of delocalization of electrons over neighboring domains, results in a marked improvement
of the calculated molecular electrostatic potential (MEP). More importantly, we show that the evaluation of the electrostatic
potential can be carried out on a dynamic framework by evaluating the free energy difference between a non-polarized MEP and
a polarized MEP. A simplified form of the potassium ion channel protein Gramicidin-A from Bacillus brevis is used as the model system for the calculation of MEP.
Figure Schematic representation of the Moving Domain QM/MM method 相似文献
14.
We present the results of simulations of a CCl4 monolayer adsorbed on a graphite surface. The CCl4 molecule was represented either by a shapeless superatom or by its atomic sites. The simulations were carried out over a
large range of temperatures, from 20 K up to 340 K. We address the following problems: (1) the influence of molecular shape
on the structure and stability of phases (particularly at low temperatures), and (2) the influence of the graphite corrugation
on layer stability and mechanism of phase transitions. In particular, we discuss the possibility and conditions of the appearance
of hexatic phase in the system.
Figure Temperature dependence of Φ6 order parameter for CCl4 monolayer adsorbed onsmooth and corrugated surfaces, in the spherical Lennard Jones (LJ) approximation.For comparison, the
order parameter calculated for MacDonald’s five-site potential is also presented 相似文献
15.
Schmuker M Schwarte F Brück A Proschak E Tanrikulu Y Givehchi A Scheiffele K Schneider G 《Journal of molecular modeling》2007,13(1):225-228
SOMMER is a publicly available, Java-based toolbox for training and visualizing two- and three-dimensional unsupervised self-organizing maps (SOMs). Various map topologies are implemented for planar rectangular, toroidal, cubic-surface and spherical projections. The software allows for visualization of the training process, which has been shown to be particularly valuable for teaching purposes.
Spread of a spherical self-organizing map (SOM) in a three-dimensional data space 相似文献
16.
Respiration rates are reported to increase exponentially with temperature. Respiration rates of woody tissues are commonly
measured as CO2 efflux rates () from that tissue. However, this paper describes clear variations in stem that were not related to temperature for the case of a young beech (Fagus sylvatica L.) and oak (Quercus robur L.) tree during the dormant season. The CO2 concentration ([CO2]) in the xylem of the beech tree showed similar temperature-independent variations. The trees were grown in a growth chamber
in which radiation patterns and temperature were kept constant. was measured with an IRGA connected to cuvettes surrounding a stem segment. Xylem [CO2] was measured in situ using a CO2 microelectrode. Depressions in and [CO2] occurred during the light period, despite equal temperatures in the light and dark period. Explanations found in literature
for discrepancies in the exponential relationship between temperature and are the influence of (1) sap flow or (2) decreased cell water content. However, (1) the variations were observed in the dormant
season, when no sap flow was observed yet, and (2) reduced cell water content was not likely to be apparent as differences
in stem transpiration rates between the dark and light period were not significant. Hence, previously formulated theories
failed to explain our results. This work therefore provides a new ground for discussion on other possible causes of daytime
depressions in . One might be the refixation of respired CO2 by corticular photosynthesis in the stem parts adjacent to the stem segment enclosed by the cuvette. 相似文献
17.
Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the κ-receptor, comparative 3D–QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions for the κ-receptor were obtained with the CoMFA standard model (q
2=0.686, r
2=0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q
2=0.678, r
2=0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r
2 values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category κ-agonists from orvinols.
相似文献
18.
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
19.
Following our recent study on triazane, we present a follow-up study on the thermodynamic properties of triazane’s unsaturated
analog, triazene. We predict optimized structural parameters, vibrational frequencies, enthalpies of formation, enthalpies
of combustion, specific enthalpies of combustion, and proton affinities. Our results indicate that the cis form of triazene
has a specific enthalpy of combustion of −15.2 kJ g−1 and the trans form has a specific enthalpy of combustion of −14.7 kJ g−1.
Figure Structures of cis- and trans-triazane, N3H3 相似文献
20.
Geometry optimizations of tetraamino-tert-butylthiacalix[4]arene (tatbtc4a) and tetraamino-tert-butylcalix[4]arene (tatbc4a) complexes with acetate, oxalate, malonate, succinate, glutarate, adipate, and pimelate were carried out using the integrated MO:MO method. Thermodynamic quantities, preorganization energies and complexation energies of these complexes were obtained at the ONIOM(B3LYP/6-31G(d):AM1) level of theory. The relative stabilities of the tatbtc4a and tatbc4a complexes with carboxylate guests are reported. The complexes tatbtc4a/malonate and tatbc4a/oxalate were found to be the most stable species. The selectivity of the tatbtc4a receptor toward to malonate with respect to oxalate, in terms of selectivity coefficient, is 9.90×102.
Figure Atom labeling of tatbtc4a/oxalate complex as a representative of host-guest system. 相似文献