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Vuk Micovic Milovan D. Ivanovic Ljiljana Dosen-Micovic 《Journal of molecular modeling》2009,15(3):267-280
An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid
receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement
with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site
under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing
to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands.
Figure Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model 相似文献
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Karhánek D Kacer P Kuzma M Splíchalová J Cervený L 《Journal of molecular modeling》2007,13(9):1009-1016
Theoretical investigation of Pt(0)-olefin organometallic complexes containing tertiary phosphine ligands was focused on the
strength of platinum-olefin electronic interaction. DFT theoretical study of electronic effects in a substantial number of
ethylene derivatives was evaluated in terms of the Pt-olefin binding energy using MP2 correlation theory. Organometallics
bearing coordinated olefins with general formula (R1R2C = CR3R4)Pt(PH3)2 [R = various substituents] had been selected, including olefins containing both electron-donor substituents as well as electron-withdrawing
groups. The stability of the corresponding complexes increases with a strengthening electron-withdrawal ability of the olefin
substituents.
Figure Representation of (CH2 = CHR)Pt(PPh3)2 and the stability chart 相似文献
6.
Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines
and their congeners as multidrug resistance-associated protein (MRP1) modulators. A five-point pharmacophore with two hydrogen
bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric
features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation
coefficient of r
2 = 0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q
2 = 0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse
compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore.
The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes
from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1
inhibitors.
Figure Alignment of multidrug resistance-associated protein (MRP1) inhibitors with the developed pharmacophore.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
7.
The microphase separation dynamics of the triblock copolymer surfactant P103 [(ethylene oxide)17(propylene oxide)60(ethylene oxide)17] was investigated by a dynamic variant of mean-field density functional theory. Different self-assembled aggregates, spherical
micelles, micellar clusters and disk-like micelles, are explored in the solution. The spherical micelle above critical micelle
concentration (CMC) is a dense core consisting mainly of PPO and a hydrated PEO swollen corona, and is in good agreement with
the experimental results concerning their structures. At a concentration of 10–15%, micellar clusters with a larger PPO core
form as a result of coalescence among spherical micelles. At concentrations above 16% by volume, a series of disk-like micelles
come into being. The order parameters show that spherical micelles are easily formed, while the micellar clusters or disk-like
micelles need a longer time to reach steady equilibrium. The results show that mesoscopic simulation can augment experimental
results on amphiphilic polymers, and provide some mesoscopic information at the mesoscale level.
Figure Coalescence of Micelles with time evolution for 15% vol system. □ represents spherical micelle that coalesce. (a) 180 μs, (b) 190 μs, (c)225 μs, and (d) 250 μs 相似文献
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We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water
molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation
method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we
have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect
effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily.
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Chun-Fang Huo Ralf Jackstell Matthias Beller Haijun Jiao 《Journal of molecular modeling》2010,16(3):431-436
The Pd-catalyzed telomerization in the presence of phosphine and carbene ligands has been computed. It is shown that the C–C
coupling of the less stable complex A with one trans- and one cis-butadiene in syn orientation forms the most stable intermediate B and is favorable both kinetically and thermodynamically. Protonation of B leads to equilibrium of the two most stable isomers of intermediate C. The overall regioselectivity is favored thermodynamically.
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12.
The geometric and electronic structure of tetracyanoethylene (TCNE)-aniline (donor-acceptor type) complex has been investigated
in gas phase using ab initio and time dependent density functional theory calculations. Both the above calculations predict a composed structure for the
complex, in which the interacting site is a C≡N and C=C bond center in the TCNE and, –NH2 and π-electrons of aniline. The N atom of aniline is oriented toward the TCNE molecule. The charge transfer transition energy,
estimated by calculating the ground-to-excited state transition electric dipole moments of the complex, agree well with the
reported experimental value in chloroform medium.
TCNE-aniline at ground state. TCNE-aniline at excited state 相似文献
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Machado NF Calheiros R Fiuza SM Borges F Gaspar A Garrido J Marques MP 《Journal of molecular modeling》2007,13(8):865-877
The conformational preferences of several potential anticancer dihydroxycinnamic esters with a variable length alkyl chain
were studied by quantum-mechanical (DFT) calculations (both for the isolated molecule and for aqueous solutions). The orientation
of the hydroxyl ring substituents and of the alkyl ester moiety relative to the carbonyl group showed these to be the most
determinant factors for the overall stability of this type of phenolic systems, strongly dependent on an effective π-electron
delocalization. Compared to the parent caffeic acid (dihydroxycinnamic acid), esterification was found to lead to a higher
conformational freedom, and to affect mainly the energy barrier corresponding to the (O=)C-OR internal rotation. No particular
differences were verified to occur upon lengthening of the ester alkyl chain, except when this is branched instead of linear.
The vibrational spectra of the whole series of compounds were simulated, based on their calculated harmonic vibrational frequencies,
and a preliminary assignment was performed.
Figure Schematic representation of the dihydroxycinnamic esters studied in the present work and of the main internal rotations affecting
the overall stability of the molecules. (R=(CH2)n, n = 0,1,2,3,7,11 for MC, EC, PC, BC, OC and DC, respectively; R=(CHCH3) for IPC. The atom numbering is included, with the exception of the alkyl ester group) 相似文献
14.
Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their
overexpression with a wide variety of cancers. As a method for the discovery of novel inhibitors of Cdc25 phosphatases, we
have evaluated the computer-aided drug design protocol involving the homology modeling of Cdc25A and virtual screening with
the two docking tools: FlexX and the modified AutoDock program implementing the effects of ligand solvation in the scoring
function. The homology modeling with the X-ray crystal structure of Cdc25B as a template provides a high-quality structure
of Cdc25A that enables the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is
found to be more accurate than FlexX in terms of scoring putative ligands. A detailed binding mode analysis of the known inhibitors
shows that they can be stabilized in the active site of Cdc25A through the simultaneous establishment of the multiple hydrogen
bonds and the hydrophobic interactions. The present study demonstrates the usefulness of the modified AutoDock program as
a docking tool for virtual screening of new Cdc25 phosphatase inhibitors as well as for binding mode analysis to elucidate
the activities of known inhibitors.
Figure Structures and available IC50 values (in μM) of the twenty Cdc25 phosphatase inhibitors seeded in docking library 相似文献
15.
Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond
cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (PIII). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that
decomposition to PIII derivatives proceeds via an elimination reaction.
Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (PIII) 相似文献
16.
Andruniów T 《Journal of molecular modeling》2007,13(6-7):775-783
Resonance Raman (RR) spectra of green fluorescent protein (GFP) model chromophores in solution have been simulated with the
CASSCF/MM methodology. Although several reports on vibrational analysis of GFP model chromophores have been recently published,
the RR spectra were simulated for the first time in explicit solution with the inclusion of the counterion, as these effects are crucial for unambiguously reproducing the vibrational
band assignment in the anionic form of the GFP chromophore. This strategy allows for a one-to-one correspondence of the calculated
vibrational modes to the observed RR bands, concerning both the location and intensity pattern. In addition, these simulations
were complemented with total energy distribution calculations to aid in the unambiguous assignment of the measured spectra.
The current study helps to clarify some of the previous RR bands assignments as well as producing some new assignment for
the anionic form of GFP chromophore. The explicit solvent simulations and PCM-based calculations are compared to the measured spectra, and these results demonstrate that explicit solvent simulations provide better agreement with experiment, both in terms of vibrational frequencies and intensity distribution.
Figure
a Correlation of explicit hydration calculations (CASSCF/6-31G*/MM) for the HBI model chromophore and experimental RR data [21]; slope = 0.982, intercept = 27.210 and regression coefficient = 0.997. b Correlation of implicit PCM calculations (CASSCF/6-31G*) for the HBI model chromophore and experimental RR data [21], slope = 1.017, intercept = −48.838 and regression coefficient = 0.984 相似文献
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Lee JY Doddareddy MR Cho YS Choo H Koh HY Kang JH No KT Pae AN 《Journal of molecular modeling》2007,13(5):543-558
Comparative quantitative structure–activity relationship (QSAR) analyses of peptide deformylase (PDF) inhibitors were performed
with a series of previously published (British Biotech Pharmaceuticals, Oxford, UK) reverse hydroxamate derivatives having
antibacterial activity against Escherichia coli PDF, using 2D and 3D QSAR methods, comparative molecular field analysis (CoMFA), comparative molecular similarity indices
analysis (CoMSIA), and hologram QSAR (HQSAR). Statistically reliable models with good predictive power were generated from
all three methods (CoMFA r
2 = 0.957, q
2 = 0.569; CoMSIA r
2 = 0.924, q
2 = 0.520; HQSAR r
2 = 0.860, q
2 = 0.578). The predictive capability of these models was validated by a set of compounds that were not included in the training
set. The models based on CoMFA and CoMSIA gave satisfactory predictive r
2 values of 0.687 and 0.505, respectively. The model derived from the HQSAR method showed a low predictability of 0.178 for
the test set. In this study, 3D prediction models showed better predictive power than 2D models for the test set. This might
be because 3D information is more important in the case of datasets containing compounds with similar skeletons. Superimposition
of CoMFA contour maps in the active site of the PDF crystal structure showed a meaningful correlation between receptor–ligand
binding and biological activity. The final QSAR models, along with information gathered from 3D contour and 2D contribution
maps, could be useful for the design of novel active inhibitors of PDF.
Figure Superimposition of comparative molecular field analysis (CoMFA) contour plot in the active site of peptide deformylase (PDF) 相似文献
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The ONIOM2 (B3LYP/6–31G (d, p): PM3) and B3LYP/6–31G (d, p) methods were applied to investigate the interaction between STI-571 and abelson tyrosine kinase binding site. The complex of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- phenyl]-benzamide (part of STI-571) and related 16 amino acid residues were found at B3LYP/6–31G (d, p) level to have hydrogen bonds and π....π stacking interaction,
their binding energy via HAF optimization was −20.4 kcal mol−1. The results derived from this study agreed well with the reported observation.
Figure Optimized structure of STI-571 and Thr315 in abelson tyrosine kinase based on ONIOM2 method 相似文献
20.
William N. Setzer 《Journal of molecular modeling》2009,15(2):197-201
Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to
obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities
of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds:
The energies of the frontier molecular orbitals (E
HOMO and E
LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6).
Figure LUMO of Pristimerin. 相似文献