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At least 523 records · Page 29Linked to original sources
PubMed1993

Changes in plasma cortisol concentration in lambs of three ages after three methods of castration and tail docking.

Lambs were handled only or castrated and tail docked at five, 21 and 42 days of age by either surgery, rubber ring or rubber ring and Burdizzo. Plasma cortisol was measured in blood samples taken before and at 12, 24, 36, 48, 60, 72, 84, 96, 138 and 180 minutes after castration and docking. Pre-treatment and peak cortisol values were highest in five-day-old lambs. The peak cortisol values, at each age, were similar for surgery and rubber ring groups. However, the peak occurred earlier after surgery and rubber ring Burdizzo than after rubber ring only treatment. The cortisol peak was 28 nmol litre-1 lower after rubber ring Burdizzo than surgery or rubber ring only. Plasma cortisol returned to pretreatment values within 84 minutes after rubber ring Burdizzo, 96 to 138 minutes after rubber ring only but not within 180 minutes after surgery. The changes in plasma cortisol together with the changes in behaviour suggest that the rubber ring Burdizzo method of castration and docking of lambs at all ages, was probably the least painful of the methods tested.

Aging↗
PubMed1995

Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: docking between the antimalarial agent and its putative receptor.

Artemisinin (qinghaosu, QHS) is a promising new antimalarial agent that is effective against drug-resistant strains of malaria. The antimalarial activity of this drug appears to be mediated by an interaction of the drug's endoperoxide bridge with intraparasitic hemin. We have carried out a computer-assisted docking of QHS with hemin from various starting configurations and found that, in the most stable docked configuration, the endoperoxide bridge is in close proximity to the hemin iron. In contrast, an inactive analog, deoxyartemisinin (DQHS), docks in a different manner. Further computer analysis of the drug-hemin interaction might aid in the design of new QHS congeners.

Antimalarials↗
PubMed1989

A non-docking intraoperative electron beam applicator system.

A non-docking intraoperative radiation therapy electron beam applicator system for a linear accelerator has been designed to minimize the mechanical, electrical, and tumor visualization problems associated with a docking system. A number of technical innovations have been used in the design of this system. These include: (a) a new intraoperative radiation therapy cone design that gives a better dose uniformity in the treatment volume at all depths; (b) a collimation system which reduces the leakage radiation dose to tissues outside the intraoperative radiation therapy cone; (c) a non-docking system with a translational accuracy of 2 mm and a rotational accuracy of 0.5 degrees; and (d) a rigid clamping system for the cones. A comprehensive set of dosimetric characteristics of the intraoperative radiation therapy applicator system is presented.

Combined Modality Therapy↗
PubMed1995

Syntaxin and synaptobrevin function downstream of vesicle docking in Drosophila.

In synaptic transmission, vesicles are proposed to dock at presynaptic active zones by the association of synaptobrevin (v-SNARE) with syntaxin (t-SNARE). We test this hypothesis in Drosophila strains lacking neural synaptobrevin (n-synaptobrevin) or syntaxin. We showed previously that loss of either protein completely blocks synaptic transmission. Here, we attempt to establish the level of this blockade. Ultrastructurally, vesicles are still targeted to the presynaptic membrane and dock normally at specialized release sites. These vesicles are mature and functional since spontaneous vesicle fusion persists in the absence of n-synaptobrevin and since vesicle fusion is triggered by hyperosmotic saline in the absence of syntaxin. We conclude that the SNARE hypothesis cannot fully explain the role of these proteins in synaptic transmission. Instead, both proteins play distinct roles downstream of docking.

Animals↗
PubMed1995

Flexible docking of peptides to class I major-histocompatibility-complex receptors.

We present a new method for docking flexible peptides to class I Major-Histocompatibility-Complex (MHC) receptors. Docking is performed in two steps: (a) The charged terminal peptide residues are located by randomly distributing multiple copies of each in volumes of approximately 150 A at either end of the binding groove, and then minimizing the system energy using a modified multiple-copy search algorithm. This is followed by (b) construction of the intervening chain using the multiple-copy bond-scaling-relaxation loop closure algorithm. In both steps, the copies tend to cluster and the size of the resulting clusters is proportional to the basin of attraction of the corresponding energy well. We show that native MHC-bound peptides have broad minima and, consequently, that misfolded, low-energy peptide conformations can be eliminated by restricting consideration to groups of peptides which cluster into broad minima. The accuracy of the method is assessed by comparing the predictions with crystallographic data for three different MHC peptide systems, at various degrees of stringency: (a) the extent to which we can determine side chain function (anchor vs. T-cell epitopes); (b) the extent to which we can determine the peptide-receptor orientation; and (c) the accuracy with which we can predict atomic coordinates. We find the method correct on (a) for 19 of the 22 non-Gly positions; the failures appearing to be a consequence of omitting solvation. Predictions related to (b) are also very encouraging, with the overall orientation of the predicted peptides being very similar to the crystal conformation, when measured by the hydrogen bonding pattern between the two. The degree of success in predicting atomic coordinates varied considerably, however, from 1.4 A for the HLA-A2 peptide to 2.7 A for the Kb peptide. The inaccuracy of the latter appears to reflect an incomplete target function, most likely the ommission of solvation. The calculations thus define the current limits of accuracy in docking flexible peptides to Class I receptors and identify the methodological improvements that must be made for the next advance in accuracy.

Algorithms↗
PubMed2004

Interaction of cytochrome c with cytochrome oxidase: two different docking scenarios.

Cytochrome c is the specific and efficient electron transfer mediator between the two last redox complexes of the mitochondrial respiratory chain. Its interaction with both partner proteins, namely cytochrome c(1) (of complex III) and the hydrophilic Cu(A) domain (of subunit II of oxidase), is transient, and known to be guided mainly by electrostatic interactions, with a set of acidic residues on the presumed docking site on the Cu(A) domain surface and a complementary region of opposite charges exposed on cytochrome c. Information from recent structure determinations of oxidases from both mitochondria and bacteria, site-directed mutagenesis approaches, kinetic data obtained from the analysis of isolated soluble modules of interacting redox partners, and computational approaches have yielded new insights into the docking and electron transfer mechanisms. Here, we summarize and discuss recent results obtained from bacterial cytochrome c oxidases from both Paracoccus denitrificans, in which the primary electrostatic encounter most closely matches the mitochondrial situation, and the Thermus thermophilus ba(3) oxidase in which docking and electron transfer is predominantly based on hydrophobic interactions.

Catalytic Domain↗
PubMed2003

Analysis of the full-length integrase-DNA complex by a modified approach for DNA docking.

A model of the full-length HIV-1 integrase dimer was constructed assembling the experimentally determined structures of the single domains. Subsequently, the three-domain protein-viral DNA complex was generated for the first time through an automated docking algorithm, obtained modifying the ESCHER program, a well-known method for protein-protein docking. A detailed study of the contacts established with DNA by the enzyme revealed that the predicted model reproduced the results of mutagenesis and cross-linking experiments, confirming the validity of our docking approach in predicting the base specificity in the DNA-protein interaction.

Base Sequence↗
PubMed2006

Evidence that the MAPK-docking site in MAPKK Dpbs2p is essential for its function.

In eukaryotes, mitogen-activated protein kinase (MAPK) pathways are very important signal transduction modules that regulate various cellular processes. Although eukaryotic cells possess a number of MAP kinase pathways, normally the MAPKKs selectively activate their cognate MAPK. Recent studies suggest that the MAPK-docking site in MAPKK facilitates this specific recognition and activation. However, the role of the docking site under in vivo conditions has not been demonstrated. In yeast external high osmolarity activates HOG (high osmolarity glycerol) MAPK pathway that consists of MAPKKK (Ste11p or Ssk2p/Ssk22p), MAPKK (Pbs2p), and MAPK (Hog1p). Previously, we have isolated a Pbs2p homologue (Dpbs2p) from osmo-tolerant and salt-tolerant yeast Debaryomyces hansenii that complemented pbs2 mutation in Saccharomyces cerevisiae. Here we show, for the first time, the presence of a MAPK-docking domain in Dpbs2p that is essential for its function in vivo. Mutation in this motif completely abolished its binding to Hog1p in vitro.

Binding Sites↗
PubMed2004

Probing the location of the substrate binding site of ascorbate oxidase near type 1 copper: an investigation through spectroscopic, inhibition and docking studies.

The present investigation addresses the problem of the binding mode of phenolic inhibitors and the substrate ascorbate to the active site of ascorbate oxidase. The results from both types of compounds indicate that the binding site is located in a pocket near the type 1 copper center. This information is of general interest for blue multicopper oxidases. Docking calculations performed on the ascorbate oxidase-ascorbate complex show that binding of the substrate occurs in a pocket near type 1 Cu, and is stabilized by at least five hydrogen bonding interactions with protein residues, one of which involves the His512 Cu ligand. Similar docking studies show that the isomeric fluorophenols, which act as competitive inhibitors toward ascorbate, bind to the enzyme in a manner similar to ascorbate. The docking calculations are supported by 19F NMR relaxation measurements performed on fluorophenols in the presence of the enzyme, which show that the bound inhibitors undergo enhanced relaxation by the paramagnetic effect of a nearby Cu center. Unambiguous support to the location of the inhibitor close to type 1 Cu was obtained by comparative relaxation measurements of the fluorophenols in the presence of the ascorbate oxidase derivative where a Zn atom selectively replaces the paramagnetic type 2 Cu. The latter experiments show that contribution to relaxation of the bound inhibitors by the type 2 Cu site is negligible.

Ascorbate Oxidase↗
PubMed2004

Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor.

In the present study, we have used an approach combining protein structure modeling, molecular dynamics (MD) simulation, automated docking, and 3D QSAR analyses to investigate the detailed interactions of CCR5 with their antagonists. Homology modeling and MD simulation were used to build the 3D model of CCR5 receptor based on the high-resolution X-ray structure of bovine rhodopsin. A series of 64 CCR5 antagonists, 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes, were docked into the putative binding site of the 3D model of CCR5 using the docking method, and the probable interaction model between CCR5 and the antagonists were obtained. The predicted binding affinities of the antagonists to CCR5 correlate well with the antagonist activities, and the interaction model could be used to explain many mutagenesis results. All these indicate that the 3D model of antagonist-CCR5 interaction is reliable. Based on the binding conformations and their alignment inside the binding pocket of CCR5, three-dimensional structure-activity relationship (3D QSAR) analyses were performed on these antagonists using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Both CoMFA and CoMSIA provide statistically valid models with good correlation and predictive power. The q(2)(r(cross)(2)) values are 0.568 and 0.587 for CoMFA and CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were not included in the training set. Mapping these models back to the topology of the active site of CCR5 leads to a better understanding of antagonist-CCR5 interaction. These results suggest that the 3D model of CCR5 can be used in structure-based drug design and the 3D QSAR models provide clear guidelines and accurate activity predictions for novel antagonist design.

Binding Sites↗
PubMed2005

Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphatase YopH inhibitors.

Three-dimensional quantitative structure-activity relationship (QSAR) studies were conducted on two classes of recently explored compounds with known YopH inhibitory activities. Docking studies were employed to position the inhibitors into the YopH active site to determine the probable binding conformation. Good correlations between the predicated binding free energies and the inhibitory activities were found for two subsets of phosphate mimetics: alpha-ketocarboxylic acid and squaric acid (R2=0.70 and 0.68, respectively). The docking results also provided a reliable conformational alignment scheme for 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed based on the docking conformations, giving q2 of 0.734 and 0.754 for CoMFA and CoMSIA models, respectively. The 3D-QSAR models were significantly improved after removal of an outlier (q2=0.829 for CoMFA and q2=0.837 for CoMSIA). The predictive ability of the models was validated using a set of compounds that were not included in the training set. Mapping the 3D-QSAR models to the active site of YopH provides new insight into the protein-inhibitor interactions for this enzyme. These results should be applicable to the prediction of the activities of new YopH inhibitors, as well as providing structural implications for designing potent and selective YopH inhibitors as antiplague agents.

Bacterial Outer Membrane Proteins↗
PubMed2005

A combined approach of docking and 3D QSAR study of beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors.

The enzyme FabH catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase. The pivotal role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of antibacterial and antiparasitic compounds. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies such as comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and docking simulations were conducted on a series of potent benzoylaminobenzoic acids. Docking studies were employed to position the inhibitors into the FabH active site to determine the probable binding conformation. A reasonable correlation between the predicated binding free energy and the inhibitory activity was found. CoMFA and CoMSIA were performed based on the docking conformations, giving q(2) of 0.637 and 0.697 for CoMFA and CoMSIA models, respectively. The predictive ability of the models was validated using a set of compounds that were not included in the training set and progressive scrambling test. Mapping the 3D QSAR models to the active site of FabH related that some important amino acid residues are responsible for protein-inhibitor interaction. These results should be applicable to the prediction of the activities of new FabH inhibitors, as well as providing structural understanding.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗
PubMed2006

Essential structural profile of a dual functional inhibitor against cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): molecular docking and 3D-QSAR analyses on DHDMBF analogues.

It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX, both are key enzymes involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig out helpful information in designing dual functional inhibitors against the two enzymes, homology modeling, molecular dynamics (MD) simulations, automated docking, and 3D-QSAR analyses were performed in this study on 21 COX-2/5-LOX dual inhibitors, namely, 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (DHDMBF) analogues. A 3D-model of 5-LOX was built based on the high-resolution X-ray structure of rabbit reticulocyte 15-lipoxygenase. Molecular docking was then applied to locate the binding orientations and conformations of DHDMBF analogues with COX-2 and 5-LOX, respectively, leading to highly predictive CoMFA models constructed on the basis of the binding conformations with q2 values of 0.782 and 0.634 for COX-2 and 5-LOX, respectively. In addition, CoMFA field distributions were found in good agreement with the structural characteristics of the corresponding binding sites. Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors should share a structural feature with a moderately bulky group at R2 position and a rather negatively charged group around the position of the carbonyl group of DHDMBFs. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing new NSAIDs as anti-inflammation drugs with favorable safety profile.

Amino Acid Sequence↗
PubMed2006

Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.

In the present work, several computational methodologies were combined to develop a model for the prediction of PDE4B inhibitors' activity. The adequacy of applying the ligand docking approach, keeping the enzyme rigid, to the study of a series of PDE4 inhibitors was confirmed by a previous molecular dynamics analysis of the complete enzyme. An exhaustive docking procedure was performed to identify the most probable binding modes of the ligands to the enzyme, including the active site metal ions and the surrounding structural water molecules. The enzyme-inhibitor interaction enthalpies, refined by using the semiempirical molecular orbital approach, were combined with calculated solvation free energies and entropy considerations in an empirical free energy model that enabled the calculation of binding free energies that correlated very well with experimentally derived binding free energies. Our results indicate that both the inclusion of the structural water molecules close to the ions in the binding site and the use of a free energy model with a quadratic dependency on the ligand free energy of solvation are important aspects to be considered for molecular docking investigations involving the PDE4 enzyme family.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Docking studies on monoamine oxidase-B inhibitors: estimation of inhibition constants (K(i)) of a series of experimentally tested compounds.

Monoamine oxidase (EC1.4.3.4; MAO) is a mitochondrial outer membrane flavoenzyme that catalyzes the oxidation of biogenic amines. It has two distinct isozymic forms designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant and neuroprotective drugs. Elucidation of the X-ray crystallographic structure of MAO-B has opened the way for molecular modeling studies. A series of experimentally tested (1-10) model compounds has been docked computationally to the active site of the MAO-B enzyme. The AutoDock 3.0.5 program was employed to perform automated molecular docking. The free energies of binding (DeltaG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian Genetic Algorithm (LGA) of AutoDock 3.0.5. Excellent to good correlations between the calculated and experimental K(i) values were obtained.

Crystallography, X-Ray↗
PubMed2005

Molecular docking and 3D-QSAR on 2-(oxalylamino) benzoic acid and its analogues as protein tyrosine phosphatase 1B inhibitors.

In this paper, molecular docking technique was used to investigate the binding conformation of twelve 2-(oxalylamino) benzoic acid (OBA) inhibitors in the active site of PTP1B. The predicted binding affinities are linearly correlated to the experimental values (r(2)=0.859). Furthermore, comparative molecular field analysis (CoMFA) was conducted based on the binding conformation predicted by molecular docking. The predicted CoMFA model has satisfactory statistical significance and good actual predicted power. The information from molecular docking and CoMFA may give us some valuable hints to the optimization of lead compounds.

4-Aminobenzoic Acid↗
PubMed2006

Docking studies and development of novel 5-heteroarylamino-2,4-diamino-8-chloropyrimido-[4,5-b]quinolines as potential antimalarials.

MOE-Dock (Docking software) was used to predict the binding modes of 10 novel and potent 5-substituted amino-2,4-diamino-8-chloropyrimido-[4,5-b]quinolines (compounds I-X) as part of our antimalarial drug development programme. This was done by analyzing the interaction of these compounds with the active sites of 11 enzymes present in Plasmodium falciparum and based on this, effective binding was observed to enzyme P. falciparum glutathione reductase (PfGR). The binding scores for compounds I-X with PfGR were also congruent with their antimalarial activity. Three additional analogs were then designed and synthesized based on the above docking study and the pharmacophoric requirements for this class.

Animals↗
PubMed2004

Novel knowledge-based potentials for ligand docking: variational approach to the old problem.

The variational approach of evaluation for knowledge-based potentials is considered for the first time. In this approach, the problem to derive knowledge-based potentials is solved as the optimization task in the multiparametric model of atom types, reference states and interaction cutoff radii. Using analogy to liquid state theory we offered four new reference states and derived corresponding knowledge-based potentials. The cutoff radii and atom types are optimized to minimize averaged root-mean square deviations (RMSD) of the ligand docked positions regarding to the experimentally determined poses. The number of atom types is varied on the developed atom type tree with 6 root (C, N, O, S, P and the halogen type) and 49 apical atom types. We showed a pronounced effect of atom type choice on docking accuracy and proved that splitting of elements C, N and O of the periodic system up to the 18 optimal atom types essentially improves docking accuracy.

Ligands↗