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1.
Shaikh AR Broclawik E Tsuboi H Koyama M Endou A Takaba H Kubo M Del Carpio CA Miyamoto A 《Journal of molecular modeling》2007,13(6-7):851-860
The metabolism mechanism of (S)-N-[1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide, mediated by CYP3A4 Cytochrome has been
investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. Two different
orientations of phenyl ring for substrate approach toward oxyferryl center, imposing two subsequent rearrangement pathways
have been investigated. Starting from σ-complex in perpendicular orientation enzymatic mechanism involves consecutive proton
shuttle intermediate, which further leads to the formation of alcohol and ketone. Parallel conformation leads solely to ketone
product by 1,2 hydride shift. Although parallel and perpendicular σ-complexes are energetically equivalent both for the gas
phase or PCM solvent model, molecular dynamics studies in full CYP3A4 environment show that perpendicular conformation of
the σ-complex should be privileged, stabilized by hydrophobic interactions of phenylacrylamide chain. After assessing probability
of the two conformations we postulate that the alcohol, accessible with the lowest energy barriers should be the major metabolite
for studied substrate and CYP3A4 enzyme.
Figure Orientation of phenyl ring towards porphyrin plane selected by substrate interaction with enzymatic cavity channels enzymatic
reaction 相似文献
2.
Aminoglycoside–arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1).
Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine
(PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which
may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded
envelope glycoprotein 120 (HIV-1IIIB gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs
spread over two negatively charged patches of CXCR4. PA-Neo-PA–CXCR4 complexes are energetically more favorable than AACs/APAC–CXCR4
complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors
of gp120–CXCR4 binding without affecting stromal cell-derived factor 1α (SDF-1α) chemotaxis activity, or inhibitors of SDF-1α–CXCR4
binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4–gp120 binding
in unliganded conformation.
Figure The r5-Neo-r5-CXCR4 complex. CXCR4 is shown in CPK representation. The negatively charged residues are shown in red and positively charged residues in blue. The r5-Neo-r5 is shown in stick representation, neomycin core is colored yellow and arginine moieties are colored magenta. Two negatively charged patches separated by neutral and positively charged residues are visible. 相似文献
3.
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
4.
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
5.
The electrode potential of 2-(4,5-dihydroxy-2-methylphenyl)-2-phenyl-2H-indene-1,3-dione (DMPID) in acetonitrile has been calculated. The calculations were performed using ab initio molecular orbital
calculations (HF), and density functional theory (DFT) with the inclusion of entropic and thermochemical corrections to yield
free energies of redox reactions. The electrode potential of DMPID was also obtained experimentally with the aid of an electrochemical
technique (cyclic voltammetry). The values for geometric parameters and the vibrational frequencies of DMPID and 2-(6-methyl-3,4-dioxocyclohexa-1,5-dienyl)-2-phenyl-2H-indene-1,3-dione
(MDPID) were also computed using the same levels with the basis set of 6-31G(d). The calculated IR spectrum of DMPID used
for the assignment of IR frequencies was observed in the experimental FT-IR spectrum and the calculated IR and FT-IR observed
spectra of DMPID were compared with correlation factor of 0.996. It should be mentioned that the present work is the first
research on coagulant derivative molecules in which the electrode potential of a molecule is calculated.
Optimized structures of 2-(6-methyl-3,4-dioxocyclohexa-1,5-dienyl)-2-phenyl-2H-indene-1,3-dione (MDPID) 相似文献
6.
The molecular geometries, normal mode frequencies, intensities and corresponding infrared assignments of monomeric and dimeric
2,3-dimethylpyridine, 2,4-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine and monomeric 2,6-dimethylpyridine
in the ground state were investigated at the density functional theory (DFT)-B3LYP level using the 6-311+G(d, p) basis set.
The vibrational frequencies and geometric parameters of C–H stretching and bending in the fundamental region were calculated
and compared to the Fourier transform infrared (FT-IR) data obtained. In the studied monomeric and dimeric dimethyl substituted
pyridine derivatives, the C–H stretching and bending frequency shifts that occur between the dimer and the monomer may be
diagnostic of the magnitude of dimerization energy. As supported by data in the literature, the most stable dimeric form was
obtained for the 3,4-dimethylpyridine molecule.
Figure Molecular model and numbering scheme of the studied dimeric dimethylpyridinederivatives 相似文献
7.
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
8.
Mendieta-Wejebe JE Rosales-Hernández MC Rios H Trujillo-Ferrara J López-Pérez G Tamay-Cach F Ramos-Morales R Correa-Basurto J 《Journal of molecular modeling》2008,14(6):537-545
Cytochrome P-450 is a group of enzymes involved in the biotransformation of many substances, including drugs. These enzymes
possess a heme group (1) that when it is properly modified induces several important physicochemical changes that affect their enzymatic activity.
In this work, the five structurally modified heme derivatives 2–6 and the native heme 1 were docked on CYP2B4, (an isoform of P450), in order to determine whether such modifications alter their binding form and
binding affinity for CYP2B4 apoprotein. In addition, docking calculations were used to evaluate the affinity of CYP2B4 apoprotein-heme
complexes for aniline (A) and N-methyl-aniline (NMA). Results showing the CYP2B4 heme 4- and heme 6-apoprotein complexes to be most energetically stable indicate that either hindrance effects or electronic properties are
the most important factors with respect to the binding of heme derivatives at the heme-binding site. Furthermore, although
all heme-apoprotein complexes demonstrated high affinity for both A and NMA, the CYP2B4 apoprotein-5 complex had higher affinity for A, and the heme 6 complex had higher affinity for NMA. Finally, surface electronic properties (SEP) were calculated in order to explain why
certain arginine residues of CYP2B4 apoprotein interact with polarizable functionalities, such as ester groups or sp
2
carbons, present in some heme derivates. The main physicochemical parameter involved in the recognition process of the heme
derivatives, the CYP2B4 apoprotein and A or NMA, are reported.
Figure Scheme of steps to be followed for obtaining five new CYP2B4 apoprotein-heme complexes by docking 相似文献
9.
Jarosław J. Panek Thomas R. Ward Aneta Jezierska Marjana Novič 《Journal of molecular modeling》2009,15(3):257-266
Due to its highly specific and very strong binding, the (strept)avidin–biotin system forms the basis for numerous applications
in the life sciences: immunoassays, DNA detection systems, affinity chromatography, etc. Fine-tuning of the ligand binding
abilities of this system might provide new technologies with relevance to nanoscale research. Here, we report our computational
investigations on wild type (WT) and modified streptavidin (SAV), assessing the impact of fluorination of tryptophan residues
on biotin binding ability. Complexes of biotin with four SAV protein variants (WT-SAV, 4fW-SAV, 5fW-SAV and 6fW-SAV) were
studied. We found that protein stability and folding are predicted to be weakly affected by fluorination. The host protein
binding pocket decreases its ability to form numerous hydrogen bonds to biotin in the case of the 4fW-SAV variant. Conversely,
the 5fW-SAV mutant is predicted to have an even more stable ligand–host hydrogen bonding network than WT-SAV. Thermodynamic
perturbation investigations predict a decrease in biotin binding free energy from 3.0 to 6.5 kcal/mol per tetrameric host,
with the 5fW-SAV mutant being least affected. Overall, the computational findings indicate that 6fW-SAV and, especially, 5fW-SAV
to be promising variants of streptavidin for potential modifiable picomolar binding of the biotin ligand family.
Figure Hydrogen bonding framework of the biotin–streptavidin system
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
10.
Semi-empirical quantum mechanics calculations using AM1 (Austin Method 1) were carried out for various host-guest combinations of α-cyclodextrin and mono-halogen benzoic acids. The energetically favorable inclusion structures were identified. The AM1 results show that α-cyclodextrin complexes with mono-halogen benzoic acid acids (where the halogen is chlorine, bromide, iodine) as guest compounds are more stable in the “head first” position than in the “tail-first” position for meta and para isomers while ortho mono-halogen benzoic acids complexes with α-cyclodextrin are more stable in “tail-first” position. The calculated structures were found to be in good agreement with those obtained from crystalographic databases.
相似文献
11.
Ankyrin repeat proteins (ARPs) appear to be abundant in organisms from all phyla, and play critical regulatory roles, mediating
specific interactions with target biomolecules and thus ordering the sequence of events in diverse cellular processes. ARPs
possess a non-globular scaffold consisting of repeating motifs named ankyrin (ANK) repeats, which stack on each other. The
modular architecture of ARPs provides a new paradigm for understanding protein stability and folding mechanisms. In the present
study, the stability of various C-terminal fragments of the ARP p18INK4c was investigated by all-atomic 450 ns molecular dynamics (MD) simulations in explicit water solvent. Only motifs with at
least two ANK repeats made stable systems in the available timescale. All smaller fragments were unstable, readily losing
their native fold and α-helical content. Since each non-terminal ANK repeat has two hydrophobic sides, we may hypothesize
that at least one hydrophobic side must be fully covered and shielded from the water as a necessary, but not sufficient, condition
to maintain ANK repeat stability. Consequently, at least two ANK repeats are required to make a stable ARP.
Figure Structure of the p18INK4c protein (PDB entry 1IHB, chain B), which is a member of the cyclin-dependent kinase inhibitor (INK)
tumor suppressor family with five ankyrin (ANK) repeat modules. The figure was generated by PyMol
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
12.
Setzer WN 《Journal of molecular modeling》2008,14(5):335-342
The energetics of the Cope rearrangement of 17 germacrane sesquiterpenoids to their respective elemane forms have been calculated
using both density functional theory (B3LYP/6-31G*) and post Hartee-Fock (MP2/6-31G**) ab initio methods. The calculations are in qualitative agreement with experimentally observed Cope rearrangements, but the two methods
give slightly different results. MP2 calculations generally show more favorable elemene energies compared to the respective
germacrenes (by around 3–4 kcal mol−1) and smaller activation energies (by 2–3 kcal mol−1). Additionally, neither method is accurate enough to consistently reproduce the germacrene/elemene equilibrium. Apparently,
the generally small energy differences between the two forms in these sesquiterpenoids cannot be adequately reproduced at
these levels of calculation.
Figure The Cope rearrangement of the germacrane sesquiterpenoid bacchascandon to the elemane shyobunone 相似文献
13.
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
14.
15.
Eight H-bonded complexes between serotonin (5-hydroxy-tryptamine) and water/hydrogen peroxide were studied at the B3LYP and
HF levels of theory, using the 6-31+G(d) basis set. A thermodynamic analysis was performed in order to find the most stable
complex. The calculated bonding parameters showed that the most stable H-bonded complex is formed between serotonin and hydrogen
peroxide by means of the intermolecular H-bond –H2N...H–OOH.
Fig. a Theoretical study of the hydrogen-bonded supersystems serotonin-water/hydrogen peroxide 相似文献
16.
The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels–Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis. Each pose is scored and ranked based on its molecular-mechanics docking energy. The reverse-docking procedure reveals a clear energetic trend in favor of the experimentally preferred product enantiomers. Analysis of the best poses suggests a geometric model that is consistent with principles of molecular recognition, catalysis, and experimental data.
相似文献
17.
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
18.
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
19.
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
20.
Effects of explicit consideration of charges displaced from atomic sites due to atomic orbital hybridization called hybridization-displaced
charges (HDC) on dipole moments and surface molecular electrostatic potentials of certain radicals and their complexes with
closed-shell molecules have been studied. HDC were computed for several radicals and their complexes at the B3LYP/6–31G**
level of theory. At this level, HDC consist of three point charges associated with hydrogen atoms and seven point charges
associated with heavy atoms belonging to the second row of the periodic table. HDC are so calculated that the contribution
of each atom to the component of molecular dipole moment arising due to atomic orbital hybridization is preserved. It is found
that dipole moments and electrostatic potentials of the systems studied here can be obtained with a significantly improved
accuracy using a combination of Mulliken charges and HDC over that obtained by Mulliken charges only.
Figure Surface MEP map of H2O-HO· radical complex obtained using Mulliken charges combined with HDC 相似文献