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Docking
Kinds of Docking Terms modified by Docking Selected AbstractsScoring ligand similarity in structure-based virtual screeningJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2009Maria I. Zavodszky Abstract Scoring to identify high-affinity compounds remains a challenge in virtual screening. On one hand, protein,ligand scoring focuses on weighting favorable and unfavorable interactions between the two molecules. Ligand-based scoring, on the other hand, focuses on how well the shape and chemistry of each ligand candidate overlay on a three-dimensional reference ligand. Our hypothesis is that a hybrid approach, using ligand-based scoring to rank dockings selected by protein,ligand scoring, can ensure that high-ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site. Results from applying this approach to screen nearly 70,000 National Cancer Institute (NCI) compounds for thrombin inhibitors tend to support the hypothesis. EON ligand-based ranking of docked molecules yielded the majority (4/5) of newly discovered, low to mid-micromolar inhibitors from a panel of 27 assayed compounds, whereas ranking docked compounds by protein,ligand scoring alone resulted in one new inhibitor. Since the results depend on the choice of scoring function, an analysis of properties was performed on the top-scoring docked compounds according to five different protein,ligand scoring functions, plus EON scoring using three different reference compounds. The results indicate that the choice of scoring function, even among scoring functions measuring the same types of interactions, can have an unexpectedly large effect on which compounds are chosen from screening. Furthermore, there was almost no overlap between the top-scoring compounds from protein,ligand versus ligand-based scoring, indicating the two approaches provide complementary information. Matchprint analysis, a new addition to the SLIDE (Screening Ligands by Induced-fit Docking, Efficiently) screening toolset, facilitated comparison of docked molecules' interactions with those of known inhibitors. The majority of interactions conserved among top-scoring compounds for a given scoring function, and from the different scoring functions, proved to be conserved interactions in known inhibitors. This was particularly true in the S1 pocket, which was occupied by all the docked compounds. Copyright © 2009 John Wiley & Sons, Ltd. [source] Docking and homology modeling explain inhibition of the human vesicular glutamate transportersPROTEIN SCIENCE, Issue 9 2007Jonas Almqvist Abstract As membrane transporter proteins, VGLUT1,3 mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. This function is crucial for exocytosis and the role of glutamate as the major excitatory neurotransmitter in the central nervous system. The three transporters, sharing 76% amino acid sequence identity in humans, are highly homologous but differ in regional expression in the brain. Although little is known regarding their three-dimensional structures, hydropathy analysis on these proteins predicts 12 transmembrane segments connected by loops, a topology similar to other members in the major facilitator superfamily, where VGLUT1,3 have been phylogenetically classified. In this work, we present a three-dimensional model for the human VGLUT1 protein based on its distant bacterial homolog in the same superfamily, the glycerol-3-phosphate transporter from Escherichia coli. This structural model, stable during molecular dynamics simulations in phospholipid bilayers solvated by water, reveals amino acid residues that face its pore and are likely to affect substrate translocation. Docking of VGLUT1 substrates to this pore localizes two different binding sites, to which inhibitors also bind with an overall trend in binding affinity that is in agreement with previously published experimental data. [source] Docking ban a non-issue to Scandanavian breedersAUSTRALIAN VETERINARY JOURNAL, Issue 2 2000Jouko Koppinen No abstract is available for this article. [source] Endo- and exo-inulinases: Enzyme-substrate interaction and rational immobilizationBIOTECHNOLOGY PROGRESS, Issue 2 2010Alessandra Basso Abstract Three-dimensional models of exoinulinase from Bacillus stearothermophilus and endoinulinase from Aspergillus niger were built up by means of homology modeling. The crystal structure of exoinulinase from Aspergillus awamori was used as a template, which is the sole structure of inulinase resolved so far. Docking and molecular dynamics simulations were performed to investigate the differences between the two inulinases in terms of substrate selectivity. The analysis of the structural differences between the two inulinases provided the basis for the explanation of their different regio-selectivity and for the understanding of enzyme-substrate interactions. Surface analysis was performed to point out structural features that can affect the efficiency of enzymes also after immobilization. The computational analysis of the three-dimensional models proved to be an effective tool for acquiring information and allowed to formulate an optimal immobilized biocatalyst even more active that the native one, thus enabling the full exploitation of the catalytic potential of these enzymes. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 [source] Insights into Multienzyme Docking in Hybrid PKS,NRPS Megasynthetases Revealed by Heterologous Expression and Genetic EngineeringCHEMBIOCHEM, Issue 8 2010Yanyan Li A critical test: We have used Red/ET recombination in a heterologous expression vector to site-specifically modify the pathway to the myxobacterial metabolite myxothiazol. Our mutagenesis results strengthen an existing model for interpolypeptide "docking" during biosynthesis of such hybrid polyketide,nonribosomal peptide natural products. [source] Crystal Structure Analysis and in Silico pKa Calculations Suggest Strong pKa Shifts of Ligands as Driving Force for High-Affinity Binding to TGTCHEMBIOCHEM, Issue 4 2009Tina Ritschel Abstract Expandedlin -benzoguanines exhibit binding affinities to tRNA-guanine transglycosylase (TGT) in the low-nanomolar range. A significant pKa shift is observed for the inhibitors moving from aqueous solution to protein environment. The protonation of the inhibitor facilitates a charge-assisted hydrogen bond in the protein,ligand complex. A novel ligand series is presented to inhibit tRNA-guanine transglycosylase (TGT), a protein with a significant role in the pathogenicity mechanism of Shigella flexneri, the causative agent of Shigellosis. The enzyme exchanges guanine in the wobble position of tRNAAsn,Asp,His,Tyr against a modified base. To prevent the base-exchange reaction, several series of inhibitors have already been designed, synthesized, and tested. One aim of previous studies was to address a hydrophobic pocket with different side chains attached to the parent skeletons. Disappointingly, no significant increase in binding affinity could be observed that could be explained by the disruption of a conserved water cluster. The ligand series examined in this study are based on the known scaffold lin -benzoguanine. Different side chains were introduced leading to 2-amino- lin -benzoguanines, which address a different pocket of the protein and avoid disruption of the water cluster. With the introduction of an amino group in the 2-position, a dramatic increase in binding affinity can be experienced. To explain this significant gain in binding affinity, Poisson,Boltzmann calculations were performed to explore pKa changes of ligand functional groups upon protein binding, they can differ significantly on going from aqueous solution to protein environment. For all complexes, a permanent protonation of the newly designed ligands is suggested, leading to a charge-assisted hydrogen bond in the protein,ligand complex. This increased strength in hydrogen bonding takes beneficial effect on binding affinity of the ligands, resulting in low-nanomolar binders. Crystal structures and docking emphasize the importance of the newly created charge-assisted hydrogen bond. A detailed analysis of the crystal structures in complex with substituted 2-amino- lin -benzoguanines indicate pronounced disorder of the attached side chains addressing the ribose 33 binding pocket. Docking suggests multiple orientations of these side chains. Obviously, an entropic advantage of the residual mobility experienced by these ligands in the bound state is beneficial and reveals an overall improved protein binding. [source] The Structural Basis for Docking in Modular Polyketide BiosynthesisCHEMBIOCHEM, Issue 3 2006Kira J. Weissman Dr. Abstract Polyketide natural products such as erythromycin and rapamycin are assembled on polyketide synthases (PKSs), which consist of modular sets of catalytic activities distributed across multiple protein subunits. Correct protein,protein interactions among the PKS subunits which are critical to the fidelity of biosynthesis are mediated in part by "docking domains" at the termini of the proteins. The NMR solution structure of a representative docking domain complex from the erythromycin PKS (DEBS) was recently solved, and on this basis it has been proposed that PKS docking is mediated by the formation of an intermolecular four - ,-helix bundle. Herein, we report the genetic engineering of such a docking domain complex by replacement of specific helical segments and analysis of triketide synthesis by mutant PKSs in vivo. The results of these helix swaps are fully consistent with the model and highlight residues in the docking domains that may be targeted to alter the efficiency or specificity of subunit,subunit docking in hybrid PKSs. [source] Design, Synthesis, Docking and Antitumor Activity of Quinazolino [3, 4-a] thieno [3, 2-d] pyrimidin-8-one DerivativesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2010Youguang Zheng Several novel quinazolino [3, 4-a] thieno [3, 2-d] pyrimidin-8-one derivatives were synthesized. All of the compounds were determined against MiaPaCa2 and DU145 cells in vitro, and the crystal structures of analog 8 and 20 in the active site of the EGFR complexes were presented. The entire compounds had been identified by 1HNMR, 13CNMR, IR, MS and EA. [source] Signposts of Docking and Scoring in Drug DesignCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2007Osman A .B. S. M. Gani Docking and scoring tools are often used in the early stages of drug discovery projects today. Because the language of this field of drug design often includes intermingled terms of physics, chemistry, biology, and medicine, the significant developments of docking and scoring are challenging to follow for non-experts. In this Science Philosophy article, I attempt to clarify the concepts used in docking and scoring to help articulate the successes and limitations of this multidisciplinary field in more comprehensible manner. [source] Design of Novel N-(2,4-Dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines [cf. (VII), (XI)] as Thymidine Phosphorylase Inhibitors, and Flexible Docking to a Homology Model.CHEMINFORM, Issue 23 2003Melissa L. P. Price No abstract is available for this article. [source] Combined Pharmacophore Modeling, Docking, and 3D QSAR Studies of ABCB1 and ABCC1 Transporter InhibitorsCHEMMEDCHEM, Issue 11 2009Abstract Quinazolinones, indolo- and pyrrolopyrimidines with inhibitory effects toward ABCB1 (P-gp) and ABCC1 (MRP1) transporters were studied by pharmacophore modeling, docking, and 3D QSAR to describe the binding preferences of the proteins. The pharmacophore overlays between dual and/or highly selective inhibitors point to binding sites of different topology and physiochemical properties for MRP1 and P-gp. Docking of selective inhibitors into the P-gp binding cavity by the use of a structural model based on the recently resolved P-gp structure confirms the P-gp pharmacophore features identified, and reveals the interactions of some functional groups and atoms in the structures with particular protein residues. The 3D QSAR analysis of the dual-effect inhibitors allows satisfactory prediction of the selectivity index of the compounds and outlines electrostatics as most important for selectivity. The results from the combined modeling approach complement each other and could improve our understanding of the protein,ligand interactions involved, and could aid in the development of highly selective and potent inhibitors of P-gp and MRP1. [source] Elastic Potential Grids: Accurate and Efficient Representation of Intermolecular Interactions for Fully Flexible DockingCHEMMEDCHEM, Issue 8 2009Sina Kazemi Potential fields represented by irregular, deformable 3D grids provide an accurate and efficient lookup table function for evaluating intermolecular interactions in docking algorithms that consider target flexibility. Target movements can be translated into appropriate displacements of grid intersection points in a binding site region if the irregular deformable 3D grid is modeled as a homogeneous linear elastic body. [source] Modeling of the Intestinal Peptide Transporter hPepT1 and Analysis of Its Transport Capacities by Docking and Pharmacophore MappingCHEMMEDCHEM, Issue 12 2008Alessandro Pedretti Dr. Abstract An early pharmacokinetic screen for peptidomimetic drugs should have the ability to predict molecules with high affinity for intestinal transporters, as peptide-like derivatives are seldom absorbed passively. Hence, the first objective of this study was to generate a reliable model for the structure of the hPepT1 protein, which is the main intestinal transporter involved in the absorption of both dietary peptides and peptidomimetics. The modeling was based on the resolved structure of the homologous bacterial lactose permease LacY using a fragmental strategy. The interaction capacities of the hPepT1 model were explored by docking a set of 50 known ligands. Despite the known predilection of hPepT1 for hydrophobic ligands, docking results unveiled the key role of the polar interactions stabilized by charged termini, especially concerning the ammonium head group. The docking results were further verified by developing a pharmacophore model that confirmed the key features required for optimal hPepT1 affinity. The consistency of the docking results and the agreement with the pharmacophore model afford an encouraging validation for the proposed model and suggest that it can be exploited to design peptide-like molecules with an improved affinity for such a transporter. [source] Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural PolyphenolsCHEMMEDCHEM, Issue 12 2007Marco Abstract Aromatase, an enzyme of the cytochrome,P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti-aromatase activity of a set of natural polyphenolic compounds was evaluated in,vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti-aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques based on grid-independent descriptors and molecular interaction fields, the major physicochemical features associated with inhibitory activity were disclosed, and a putative virtual active site of aromatase was proposed. Docking of the inhibitors into a 3D homology model structure of the enzyme defined a common binding mode for the small molecules under investigation. The good correlation between computational and biological results provides the first rationalization of the anti-aromatase activity of polyphenolic compounds. Moreover, the information generated in this approach should be further exploited for the design of new aromatase inhibitors. [source] Synthesis, Cruzain Docking, and in,vitro Studies of Aryl-4-Oxothiazolylhydrazones Against Trypanosoma cruziCHEMMEDCHEM, Issue 9 2007Cristina, Lima Leite Prof. Abstract Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target. Herein we describe a small library of aryl-4-oxothiazolylhydrazones that have been tested in assays against T.,cruzi cell cultures. The docking studies carried out suggest that these compounds are potential ligands for the TCC enzyme. The most promising compound of this series, N -(4-oxo-5-ethyl-2,-thiazolin-2-yl)- N,-phenylthio-(Z)-ethylidenehydrazone (6,f), was shown to be very active at non-cytotoxic concentrations in in,vitro assays with mammalian cells and has a potency comparable with reference drugs such as nifurtimox (Nfx) and benznidazole (Bdz). [source] A three-dimensional model of the U1 small nuclear ribonucleoprotein particleENTOMOLOGICAL RESEARCH, Issue 2 2010Jason A. SOMARELLI Abstract Most of the pre-mRNAs in the eukaryotic cell are comprised of protein-coding exons and non-protein-coding introns. The introns are removed and the exons are ligated together, or spliced, by a large, macromolecular complex known as the spliceosome. This RNA-protein assembly is made up of five uridine-rich small nuclear RNAs (U1-, U2-, U4-, U5- and U6-snRNA) as well over 300 proteins, which form small nuclear ribonucleoprotein particles (snRNPs). Initial recognition of the 5, exon/intron splice site is mediated by the U1 snRNP, which is composed of the U1 snRNA as well as at least ten proteins. By combining structural informatics tools with the available biochemical and crystallographic data, we attempted to simulate a complete, three dimensional U1 snRNP from the silk moth, Bombyx mori. Comparison of our model with empirically derived crystal structures and electron micrographs pinpoints both the strengths and weaknesses in the in silico determination of macromolecular complexes. One of the most striking differences between our model and experimentally generated structures is in the positioning of the U1 snRNA stem-loops. This highlights the continuing difficulties in generating reliable, complex RNA structures; however, three-dimensional modeling of individual protein subunits by threading provided models of biological significance and the use of both automated and manual docking strategies generated a complex that closely reflects the assembly found in nature. Yet, without utilizing experimentally-derived contacts to select the most likely docking scenario, ab initio docking would fall short of providing a reliable model. Our work shows that the combination of experimental data with structural informatics tools can result in generation of near-native macromolecular complexes. [source] Butyltin compounds in sediments from the commercial harbor of Alexandria City, EgyptENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2001Assem O. Barakat Abstract Tributyltin (TBT), dibutyltin (DBT), and monobutyltin (MBT) compounds were quantitatively determined in surface-sediment samples collected from 23 sites in the commercial harbor of Alexandria City, Egypt. Butyltin concentrations in sediments varied widely depending on the sample location, ranging from less than 0.1 to 186 ng g,1 of Sn for MBT, less than 0.1 to 379 ng g,1 of Sn for DBT, and 1 to 2,067 ng g,1 of Sn for TBT. Elevated TBT concentrations, ranging from 727 to 2,067 ng g,1 of Sn were observed in harbors, marinas, and near ship-repair facilities, indicating that the butyltin-containing, antifouling paints of boats and vessels are the major source of butyltin contamination. The TBT concentration decreased rapidly away from potential source areas of boat docking and repair facilities. The high relative concentrations of TBT in the sediments indicated that degradation processes in the sediments are minor, probably due to the anoxic sedimentary conditions at the sampling sites and/or relatively fresh input of TBT to these sites. [source] Comparison of the inward- and outward-open homology models and ligand binding of human P-glycoproteinFEBS JOURNAL, Issue 23 2009Ilza K. Pajeva An homology model of human P-glycoprotein, based on the X-ray structure of the recently resolved mouse P-glycoprotein, is presented. The model corresponds to the inward-facing conformation competent for drug binding. From the model, the residues involved in the protein-binding cavity are identified and compared with those in the outward-facing conformation of human P-glycoprotein developed previously based on the Sav1866 structure. A detailed analysis of the interactions of the cyclic peptides QZ59- RRR and QZ59- SSS is presented in both the X-ray structures of mouse P-glycoprotein and the human P-glycoprotein model generated by ligand docking. The results confirm the functional role of transmembrane domains TM4, TM6, TM10 and TM12 as entrance gates to the protein cavity, and also imply differences in their functions. The analysis of the cavities in both models suggests that the ligands remain bound to the same residues during the transition from the inward- to the outward-facing conformations. The analysis of the ligand,protein interactions in the X-ray complexes shows differences in the residues involved, as well as in the specific interactions performed by the same ligand within the same protein. This observation is supported by docking of the QZ59 ligands into human P-glycoprotein, thus aiding in the understanding of the complex behavior of P-glycoprotein substrates and inhibitors. The results confirm the possibility for multispecific drug interactions of the protein, and are important for elucidating the P-glycoprotein function and ligand interactions. [source] Non-enzymatic developmental functions of acetylcholinesterase , the question of redundancyFEBS JOURNAL, Issue 20 2008Glynis Johnson Despite in vitro demonstrations of non-enzymatic morphogenetic functions in acetylcholinesterase (AChE), the AChE knockout phenotype is milder than might be expected, casting doubt upon the relevance of such functions in vivo. Functional redundancy is a possible explanation. Using in vitro findings that AChE is able to bind to laminin-111, together with detailed information about the interaction sites, as well as an epitope analysis of adhesion-inhibiting anti-AChE mAbs, we have used molecular docking and bioinformatics techniques to explore this idea, investigating structurally similar molecules that have a comparable spatiotemporal expression pattern in the embryonic nervous system. On this basis, molecules with which AChE could be redundant are the syndecans, glypicans, perlecan, the receptor tyrosine kinase Mer, and the low-density lipoprotein receptor. It is also highly likely that AChE may be redundant with the homologous neuroligins, although there is no evidence that the latter are expressed before synaptogenesis. AChE was observed to dock with Gas6, the ligand for Mer, as well as with apolipoprotein E3 (but not apolipoprotein E4), both at the same site as the laminin interaction. These findings suggest that AChE may show direct functional redundancy with one or more of these molecules; it is also possible that it may itself have a unique function in the stabilization of the basement membrane. As basement membrane molecules are characterized by multiple molecular interactions, each contributing cumulatively to the construction and stability of the network, this may account for AChE's apparently promiscuous interactions, and also for the survival of the knockout. [source] Structural model for an AxxxG-mediated dimer of surfactant-associated protein CFEBS JOURNAL, Issue 11 2004Visvaldas Kairys The pulmonary surfactant prevents alveolar collapse and is required for normal pulmonary function. One of the important components of the surfactant besides phospholipids is surfactant-associated protein C (SP-C). SP-C shows complex oligomerization behavior and a transition to ,-amyloid-like fibril structures, which are not yet fully understood. Besides this nonspecific oligomerization, MS and chemical cross-linking data combined with CD spectra provide evidence of a specific, mainly ,-helical, dimer at low to neutral pH. Furthermore, resistance to CNBr cleavage and dual NMR resonances of porcine and human recombinant SP-C with Met32 replaced by isoleucine point to a dimerization site located at the C-terminus of the hydrophobic ,-helix of SP-C, where a strictly conserved heptapeptide sequence is found. Computational docking of two SP-C helices, described here, reveals a dimer with a helix,helix interface that strikingly resembles that of glycophorin A and is mediated by an AxxxG motif similar to the experimentally determined GxxxG pattern of glycophorin A. It is highly likely that mature SP-C adopts such a dimeric structure in the lamellar bilayer systems found in the surfactant. Dimerization has been shown in previous studies to have a role in sorting and trafficking of SP-C and may also be important to the surfactant function of this protein. [source] The HOG pathway in the halophilic black yeast Hortaea werneckii: isolation of the HOG1 homolog gene and activation of HwHog1pFEMS MICROBIOLOGY LETTERS, Issue 2 2002Martina Turk Abstract The mitogen-activated protein kinase (MAPK) Hog1p plays an essential role in the yeast hyperosmotic response. A homolog of the HOG1 gene was isolated from the halophilic black yeast Hortaea werneckii encoding a putative 359 amino acid protein, HwHog1p, with high homology to Saccharomyces cerevisiae Hog1p and to other eukaryotic Hog1p homologs. HwHog1p contains a TGY motif within a protein kinase catalytic domain and a C-terminal common docking (CD) motif. Its activation by increased salinity is regulated at the posttranscriptional level. HwHog1p is located on the plasma membrane under nonstress conditions. Upon increased external salinity it is translocated from the membrane, presumably to the nucleus. [source] Synaptotagmin regulates mast cell functionsIMMUNOLOGICAL REVIEWS, Issue 1 2001Dana Baram Summary: Synaptotagmin(s) (Syts), are products of a gene family implicated in the control of Ca2+ -dependent exocytosis. Mast cells, specialized secretory cells that release mediators of inflammatory and allergic reactions in a process of regulated exocytosis, express Syt homologues and SNAREs (Soluble NSF Attachment proteins Receptors), which together with Syt constitute the core complex which mediates exocytotic vesicle docking and fusion. Rat basophilic leukemia cells (RBL-2H3), a tumor analogue of mucosal mast cells, express the Syt homologues Syt II, Syt III and Syt V. Expression of Syt I, the neuronal Ca2+ sensor, in the RBL cells, resulted in its targeting to secretory granules and in prominent potentiation and acceleration of Ca2+ -dependent exocytosis. Syt II is localized to an amine-free lysosomal compartment, which is also subjected to regulated exocytosis. Lysosomal exocytosis is negatively regulated by Syt II: overexpression of Syt II inhibited Ca2+ -triggered exocytosis of lysosomes, while suppression of Syt II expression markedly potentiated this release. These findings implicate Syt homologues as key regulators of mast cell function. We thank Drs. T.C. Sudhof, R.H. Scheller and M. Takahashi for their generous gifts of antibodies and cDNAs. [source] Studies of molecular docking between fibroblast growth factor and heparin using generalized simulated annealingINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 13 2008Samuel Silva da Rocha Pita Abstract Since the middle 70s, the main molecular docking problem consists in limitations to treat adequately the degrees of freedom of protein (or a receptor) due to the energy landscape roughness and the high computational cost. Until recently, only few algorithms considering flexible simultaneously both ligand and receptor at low computational cost were developed. As a recent proposed Statistical Mechanics, generalized simulated annealing (GSA) has been employed at diverse works concerning global optimization problems. In this work, we used this method exploring the molecular docking problem taking into account the FGF-2 and heparin complex. Since the requirements of an efficient docking algorithm are accuracy and velocity, we tested the influence of GSA parameters qA (new configuration acceptance index), qV (energy surface visiting index), and qT (temperature decreasing control) on the performance of GSADOCK program. Our simulations showed that as temperature parameter qT increases, qA parameter follows this behavior in the interval ranging from 1.1 to 2.3. We found that the GSA parameters have the best performance for the qA values ranging from 1.1 to 1.3, qV values from 1.3 to 1.5, and qT values from 1.1 to 1.7. Most of good qV values were equal or next the good qT values. Finally, the implemented algorithm is trustworthy and can be employed as a tool of molecular modeling methods. The final version of the program will be free of charge and will be accessible at our home-page or could be requested to the authors for e-mail. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] Bacillus subtilis Esterase (BS2) and its Double Mutant Have Different Selectivity in the Removal of Carboxyl Protecting GroupsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 14-15 2009Efrosini Barbayianni Abstract An esterase from Bacillus subtilis (BS2) and its double mutant E188W/M193C quickly hydrolyze n -butyl, n -propyl, methoxyethyl and allyl esters. The wild-type BS2 preferentially removes such esters from the ,-position of glutamate diesters, while the engineered enzyme has a reversed selectivity removing esters from the ,-position of glutamate diesters. Automated docking and molecular dynamic simulations were performed to understand the molecular reason for the different regioselectivity. [source] Combined Application of Galactose Oxidase and ,- N -Acetylhexosaminidase in the Synthesis of Complex Immunoactive N -Acetyl- D -galactosaminidesADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 7-8 2005Pavla Fialová Abstract A high-yield preparatory procedure for the synthesis of p -nitrophenyl 2-acetamido-2-deoxy-,- D - galacto -hexodialdo-1,5-pyranoside (2) using the galactose oxidase from Dactylium dendroides in a batch reactor was developed. Enzymatic recognition of this aldehyde and the respective uronic acid 3 obtained by NaClO2 oxidation was studied using a set of 36 fungal ,- N -acetylhexosaminidases from Acremonium, Aspergillus, Penicillium and Talaromyces genera. The aldehyde 2 was readily hydrolysed by all tested ,- N -acetylhexosaminidases but neither the uronic acid 3 nor its methyl ester 4 were accepted. Molecular modelling with docking into the active centre of the ,- N -acetylhexosaminidase from Aspergillus oryzae revealed that the aldehyde 2 is processed as a C-6 geminal diol by the enzyme. The aldehyde 2 was tested for transglycosylation reactions using GlcNAc as an acceptor. The ,- N -acetylhexosaminidase from Talaromyces flavus gave the best yields (37%) of the transglycosylation product 2-acetamido-2-deoxy-,- D - galacto -hexodialdo-1,5-pyranosyl-(1,4)-2-acetamido- 2-deoxy- D -glucopyranose, which was oxidised in situ to yield the final product 2-acetamido-2-deoxy-,- D -galactopyranosyluronic acid-(1,4)-2-acetamido-2-deoxy- D -glucopyranose (6). Compounds 3 and 6 were shown to be high-affinity ligands for two natural killer cell activation receptors, NKR-P1A and CD69. For the latter receptor they turned out to be among the best ligands described so far. This increase was obviously due to the presence of a carboxy moiety. [source] Parallel implementation of AutoDockJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3 2007Prashant Khodade Computational docking of ligands to protein structures is a key step in structure-based drug design. Currently, the time required for each docking run is high and thus limits the use of docking in a high-throughput manner, warranting parallelization of docking algorithms. AutoDock, a widely used tool, has been chosen for parallelization. Near-linear increases in speed were observed with 96 processors, reducing the time required for docking ligands to HIV-protease from 81,min, as an example, on a single IBM Power-5 processor (1.65,GHz), to about 1,min on an IBM cluster, with 96 such processors. This implementation would make it feasible to perform virtual ligand screening using AutoDock. [source] Multiple ligand simultaneous docking: Orchestrated dancing of ligands in binding sites of proteinJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 10 2010Huameng Li Abstract Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein,ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Flexible protein-protein docking based on Best-First search algorithmJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 9 2010Efrat Noy Abstract We developed a new high resolution protein-protein docking method based on Best-First search algorithm that loosely imitates protein-protein associations. The method operates in two stages: first, we perform a rigid search on the unbound proteins. Second, we search alternately on rigid and flexible degrees of freedom starting from multiple configurations from the rigid search. Both stages use heuristics added to the energy function, which causes the proteins to rapidly approach each other and remain adjacent, while optimizing on the energy. The method deals with backbone flexibility explicitly by searching over ensembles of conformations generated before docking. We ran the rigid docking stage on 66 complexes and grouped the results into four classes according to evaluation criteria used in Critical Assessment of Predicted Interactions (CAPRI; "high," "medium," "acceptable," and "incorrect"). Our method found medium binding conformations for 26% of the complexes and acceptable for additional 44% among the top 10 configurations. Considering all the configurations, we found medium binding conformations for 55% of the complexes and acceptable for additional 39% of the complexes. Introducing side-chains flexibility in the second stage improves the best found binding conformation but harms the ranking. However, introducing side-chains and backbone flexibility improve both the best found binding conformation and the best found conformation in the top 10. Our approach is a basis for incorporating multiple flexible motions into protein-protein docking and is of interest even with the current use of a simple energy function. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Protein,protein docking dealing with the unknownJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2010Irina S. Moreira Abstract Protein,protein binding is one of the critical events in biology, and knowledge of proteic complexes three-dimensional structures is of fundamental importance for the biochemical study of pharmacologic compounds. In the past two decades there was an emergence of a large variety of algorithms designed to predict the structures of protein,protein complexes,a procedure named docking. Computational methods, if accurate and reliable, could play an important role, both to infer functional properties and to guide new experiments. Despite the outstanding progress of the methodologies developed in this area, a few problems still prevent protein,protein docking to be a widespread practice in the structural study of proteins. In this review we focus our attention on the principles that govern docking, namely the algorithms used for searching and scoring, which are usually referred as the docking problem. We also focus our attention on the use of a flexible description of the proteins under study and the use of biological information as the localization of the hot spots, the important residues for protein,protein binding. The most common docking softwares are described too. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2009Garrett M. Morris Abstract We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] | ||||||||||||||||||||||||||||||||||