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1.
This article describes in a sequential fashion how ab initio quantum mechanical methods can be applied to study the pharmacophoric
features of drugs. It also describes how accurate drug–receptor interaction calculations can guide the careful design of balanced
dual inhibitors, which form an important class of second generation drugs. As an example, the authors have chosen balanced
inhibitors of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) as modern antihypertensive drugs. A unified, accurate,
in silico design approach is presented, encompassing all steps from pharmacophore derivation to complete understanding of
mechanistic aspects leading to drug design.
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2.
Gargallo R Cedano J Mozo-Villarias A Querol E Oliva B 《Journal of molecular modeling》2006,12(6):835-845
The dependence of some molecular motions in the enzyme 1,3-1,4-β-glucanase from Bacillus licheniformis on temperature changes and the role of the calcium ion in them were explored. For this purpose, two molecular dynamics simulated trajectories along 4 ns at low (300 K) and high (325 K) temperatures were generated by the GROMOS96 package. Several structural and thermodynamic parameters were calculated, including entropy values, solvation energies, and essential dynamics (ED). In addition, thermoinactivation experiments to study the influence of the calcium ion and some residues on the activity were conducted. The results showed the release of the calcium ion, which, in turn, significantly affected the movements of loops 1, 2, and 3, as shown by essential dynamics. These movements differ at low and high temperatures and affect dramatically the activity of the enzyme, as observed by thermoinactivation studies.
The first two authors contributed equally to this work 相似文献
3.
Richard A. J. O’Hair Craig M. Williams Timothy Clark 《Journal of molecular modeling》2010,16(3):559-565
We have used density-functional theory to investigate the neighboring-group stabilization of iodine, arsenic, and phosphorus-centered
oxyanion moieties in species such as deprotonated 2-iodoxybenzoic acid (IBX) and its analogs. The magnitudes of different
stabilizing effects and further candidates for analogous stabilization are analyzed.
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4.
Fábio Alberto de Molfetta Renato Ferreira de Freitas Albérico Borges Ferreira da Silva Carlos Alberto Montanari 《Journal of molecular modeling》2009,15(10):1175-1184
In this work, two different docking programs were used, AutoDock and FlexX, which use different types of scoring functions
and searching methods. The docking poses of all quinone compounds studied stayed in the same region in the trypanothione reductase.
This region is a hydrophobic pocket near to Phe396, Pro398 and Leu399 amino acid residues. The compounds studied displays
a higher affinity in trypanothione reductase (TR) than glutathione reductase (GR), since only two out of 28 quinone compounds
presented more favorable docking energy in the site of human enzyme. The interaction of quinone compounds with the TR enzyme
is in agreement with other studies, which showed different binding sites from the ones formed by cysteines 52 and 58. To verify
the results obtained by docking, we carried out a molecular dynamics simulation with the compounds that presented the highest
and lowest docking energies. The results showed that the root mean square deviation (RMSD) between the initial and final pose were very small. In addition, the hydrogen bond pattern was conserved along the
simulation. In the parasite enzyme, the amino acid residues Leu399, Met400 and Lys402 are replaced in the human enzyme by
Met406, Tyr407 and Ala409, respectively. In view of the fact that Leu399 is an amino acid of the Z site, this difference could
be explored to design selective inhibitors of TR.
Docking and molecular dynamics simulation of genuine compounds with trypanocidal activity 相似文献
5.
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
6.
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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7.
Quan Luo Yuan Yao Wei-Wei Han Yi-Han Zhou Ze-Sheng Li 《Journal of molecular modeling》2009,15(9):1125-1132
The 3D structure of a novel epoxide hydrolase from Aspergillus niger SQ-6 (sqEH) was constructed by using homology modeling
and molecular dynamics simulations. Based on the 3D model, Asp191, His369 and Glu343 were predicted as catalytic triad. The
putative active pocket is a hydrophobic environment and is rich in some important non—polar residues (Pro318, Trp282, Pro319,
Pro317 and Phe242). Using three sets of epoxide inhibitors for docking study, the interaction energies of sqEH with each inhibitor
are consistent with their inhibitory effects in previous experiments. Moreover, a critical water molecule which closes to
the His369 was identified to be an ideal position for the hydrolysis step of the reaction. Two tyrosine residues (Tyr249 and
Tyr312) are able to form hydrogen bonds with the epoxide oxygen atom to maintain the initial binding and positioning of the
substrate in the active pocket. These docked complex models can well interpret the substrate specificity of sqEH, which could
be relevant for the structural—based design of specific epoxide inhibitors.
Figure 相似文献
8.
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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9.
The interactions of the drugs amlodipine and paroxetine, which are prescribed respectively for treatment of hypertension and depression, with the metabolizing enzyme cytochrome CYP2B4 as the drug target, have been studied by molecular dynamics (MD) simulation. Poly ethylene glycol was used to control the drugs’ interactions with each other and with the target CYP2B4. Thirteen simulation systems were carefully designed, and the results obtained from MD simulations indicated that amlodipine in the PEGylated form prescribed with paroxetine in the nonPEGylated form promotes higher cytochrome stability and causes fewer fluctuations as the drugs approach the target CYP2B4 and interact with it. The simulation results led us to hypothesize that the combination of the drugs with a specific drug ratio, as proposed in this work, manifests more effective diffusivity and less instability while metabolizing with enzyme CYP2B4. Also, the active residues in the CYP2B4 enzyme that interact with the drugs were determined by MD simulation, which were consistent with the reported experimental results. 相似文献
10.
Frans T. I. Marx Johan H. L. Jordaan Hermanus C. M. Vosloo 《Journal of molecular modeling》2009,15(11):1371-1381
The productive self-metathesis reaction of 1-octene in the presence of the Phobcat precatalyst [RuCl2(Phoban-Cy)2(=CHPh)] using density functional theory was investigated and compared to the Grubbs 1 precatalyst [RuCl2(PCy3)2(=CHPh)]. At the GGA-PW91/DNP level, the geometry optimization of all the participating species and the PES scans of the various
activation and catalytic cycles in the dissociative mechanism were performed. The formation of the catalytically active heptylidene
species is kinetically and thermodynamically favored, while the formation of trans-tetradecene is thermodynamically favored.
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11.
As one of the most important antiviral drugs against 2009 influenza A (H1N1), will zanamivir be effective for the possible drug resistant mutants? To answer this question, we combined multiple molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations to study the efficiency of zanamivir over the most frequent drug-resistant strains of neuraminidase including R293K, R152K, E119A/D and H275Y mutants. The calculated results indicate that the modeled mutants of the 2009-H1N1 strains except H275Y will be significantly resistant to zanamivir. The resistance to zanamivir is mainly caused by the loss of polar interactions. The identified potential resistance sites in this study will be useful for the development of new effective anti-influenza drugs and to avoid the occurrence of the state without effective drugs to new mutant influenza strains. 相似文献
12.
Machado E Kaczmarski M Braida B Ordejón P Garg D Norman J Cheng H 《Journal of molecular modeling》2007,13(6-7):861-864
Processes for the deposition of copper films on transition metal barrier layers by means CVD using organometallic precursors
are often found to lead to poor adhesion characteristics of the grown film. By means of first-principles molecular dynamics
simulations, we show that the source of the problem is the strong reactivity of the surfaces toward the precursors, which
decompose spontaneously upon contact with the surface leading to contamination of the interface. Our simulations consider
Ti, Ta, and W as barrier layers, and Cu(hfac)-(tmvs) as precursor. In contrast, we show that surfaces of these metals properly
passivated with nitrogen, in such a way that only N atoms are exposed on the surface, are much less active and do not lead
to decomposition of the precursor. We propose this passivation procedure as a practical solution to the adhesion problem.
Figure CupraSelect on the WN (100) surface 相似文献
13.
Manhani KK Arcuri HA da Silveira NJ Uchôa HB de Azevedo WF Canduri F 《Journal of molecular modeling》2005,12(1):42-48
Cyclin-dependent kinases (CDKs) have been identified as potential targets for development of drugs, mainly against cancer. These studies generated a vast library of chemical inhibitors of CDKs, and some of these molecules can also inhibit kinases identified in the Plasmodium falciparum genome. Here we describe structural models for Protein Kinase 6 from P. falciparum (PfPK6) complexed with Roscovitine and Olomoucine. These models show clear structural evidence for differences observed in the inhibition, and may help designing inhibitors for PfPK6 generating new potential drugs against malaria.
Figure
Ribbon diagram of PfPK6 complexed with a roscovitine and b olomoucine 相似文献
14.
We performed three 3-ns molecular dynamics simulations of d(CGCGAATTCGCG)2 using the AMBER 8 package to determine the effect of salt concentration on DNA conformational transitions. All the simulations
were started with A-DNA, with different salt concentrations, and converged with B-DNA with similar conformational parameters.
However, the dynamic processes of the three MD simulations were very different. We found that the conformation transition
was slow in the solution with higher salt concentration. To determine the cause of this retardation, we performed three additional
1.5-ns simulations starting with B-DNA and with the salt concentrations corresponding to the simulations mentioned above.
However, astonishingly, there was no delayed conformation evolution found in any of the three simulations. Thus, our simulation
conclusion is that higher salt concentrations slows the A → B conformation transition, but have no effect on the final stable
structure.
Figure A-DNA and B-DNA. (a) is the canonical A-DNA, and (b) is the canonical B-DNA. Looking from the central major groove 相似文献
15.
Molecular-dynamics simulations have been used to study the diffusion of a short single model carbonic chain on the graphite
(001) surface. The calculated diffusion coefficient (D) first increases, then decreases with increasing chain length (N). This abnormal behavior is similar to polymer lateral diffusion at the solid–liquid interface. Furthermore, we have studied
the relation between the mean-square gyration radius and N.
Figure Log–log plot of the self-diffusion coefficient D versus the chain length N. The error bars are the standard deviation measured in three repeated simulations 相似文献
16.
Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain 总被引:1,自引:0,他引:1
Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial
mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such
a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral
agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular
basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein,
a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found
that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues,
thereby activating phosphorylation of NS1.
Figure Superposition of snapshots picked from the two molecular dynamic (MD) trajectories: a H5N1 NS1 homology model and b non-H5N1 NS1 crystal structure after 0 (green ribbon), 5 (blue ribbon) and 10 ns (pink ribbon) MD simulation 相似文献
17.
The conformational stability of the extended antiparallel dimer structure of Met-enkephalin in water was analyzed by examining the hydration structure of enkephalin using molecular dynamics simulations. The result shows that, despite of the hydrophicility of the terminal atoms in the pentapeptide, the main contributor for the stability of the dimer in water is the four intermolecular hydrogen bonds between the Gly2 and Phe4 groups. The three-dimensional model of the δ-opioid pharmacophore for this dimer structure was also established. Such a model was demonstrated to match the δ-opioid pharmacophore query derived from the non-peptides SIOM, TAN-67, and OMI perfectly. This result thus strongly supports the assumption that the dimer structure of Met-enkephalin is a possible δ-receptor binding conformation.
Figure Schematic model of the extended antiparallel dimer structure of Met-enkephalin 相似文献
18.
Glucagon-like peptide-1 receptor (GLP-1R) is a promising molecular target for developing drugs treating type 2 diabetes. We
have predicted the complete three-dimensional structure of GLP-1R and the binding modes of several GLP-1R agonists, including
GLP-1, Boc5, and Cpd1, through a combination of homology modeling, molecular docking, and long-time molecular dynamics simulation
on a lipid bilayer. Our model can reasonably interpret the results of a number of mutation experiments regarding GLP-1R as
well as the successful modification to GLP-1 by Liraglutide. Our model is also validated by a recently revealed crystal structure
of the extracellular domain of GLP-1R. An activation mechanism of GLP-1R agonists is proposed based on the principal component
analysis and normal mode analysis on our predicted GLP-1R structure. Before the complete structure of GLP-1R is determined
through experimental means, our model may serve as a valuable reference for characterizing the interactions between GLP-1R
and its agonists.
Figure Comparison of our predicted model of rGLP-1R (left) with the recently revealed crystal structure of hGLP-1R (right) 相似文献
19.
Glossman-Mitnik D 《Journal of molecular modeling》2007,13(1):43-46
Solanidine is the steroidal aglycon of some potato glycoalkaloids and a very important precursor for the synthesis of hormones and some pharmacologically active compounds. In this work, we make use of a new chemistry model within Density Functional Theory, called CHIH-DFT, to calculate the molecular structure of solanidine, as well to predict its infrared and ultraviolet spectra. The calculated values are compared with the experimental data available for this molecule as a means of validation of our proposed chemistry model.
Figure Molecular structure of solanidine calculated with the CHIH(small) model chemistry 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