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  • 1
    ISSN: 1573-4943
    Keywords: creatine kinase primary structure comparisons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Comparisons of nine creatine kinase sequences show that 67% of the protein sequence is identical among rabbit, rat, mouse, and chicken muscle, rabbit, rat, and chicken brain, and electric organ sequences from two species of electric ray(Torpedo). The extensive homology precludes a facile prediction of active-site residues based on sequence conservation. The sequences are more similar within isozyme types than are the different isozymes from any one species. There are 35 positions in the muscle and brain sequence pairs for three species which differentiate the two forms. TheTorpedo sequences do not fall completely into either of these patterns. Except for homology with partial sequences of other ATP-guanidino phosphotransferases, no significant homology with other protein or nucleic acid sequences in available databases was found. Preliminary secondary structural predictions suggest that the C-terminal half of the protein is likely an α/β-type protein. Placement in the sequence of two peptides found in previous cross-linking studies reveals two stretches of primary structure that are presumably close in space to the reactive Cys-283 and hence close to the active site.
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  • 2
    ISSN: 1573-4951
    Keywords: DNA docking ; Database search ; Selective DNA binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary For the first time a general shape-search docking algorithm (DOCK) has been applied to the minor and major grooves of A-, B- and Z-type DNA dodecamers and to an intercalation site in a B-DNA-type hexamer. Both experimentally and theoretically derived geometries for the various DNA fragments were used. The DOCK searches were carried out on a subset of the Cambridge Crystallographic Database, consisting of almost 10 000 molecules. One of the molecules that scored best in terms of the DOCK algorithm was CC-1065, a potent antitumor agent known to (covalently) bind the AT-rich parts of the minor groove of B-DNA. Several known DNA-binding agents also scored highly. Molecules with shapes complementary to A-, B- and Z-type DNA were indicated by DOCK. In addition, compounds were extracted from the database that might be selective for the GC-rich regions of the minor groove of B-DNA. Many of the compounds in the present study may serve as a starting point for further molecular design of novel DNA-binding ligands.
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  • 3
    ISSN: 1573-4951
    Keywords: Molecular recognition ; Configurational sampling ; Ligand docking ; Structure-based drug design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Strategies for computational association of molecular components entail a compromise between configurational exploration and accurate evaluation. Following the work of Meng et al. [Proteins, 17 (1993) 266], we investigate issues related to sampling and optimization in molecular docking within the context of the DOCK program. An extensive analysis of diverse sampling conditions for six receptor-ligand complexes has enabled us to evaluate the tractability and utility of on-the-fly force-field score minimization, as well as the method for configurational exploration. We find that the sampling scheme in DOCK is extremely robust in its ability to produce configurations near to those experimentally observed. Furthermore, despite the heavy resource demands of refinement, the incorporation of a rigid-body, grid-based simplex minimizer directly into the docking process results in a docking strategy that is more efficient at retrieving experimentally observed configurations than docking in the absence of optimization. We investigate the capacity for further performance enhancement by implementing a degeneracy checking protocol aimed at circumventing redundant optimizations of geometrically similar orientations. Finally, we present methods that assist in the selection of sampling levels appropriate to desired result quality and available computational resources.
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  • 4
    ISSN: 1573-4951
    Keywords: backtrack algorithm ; conformation ; de novo ; diversity ; incremental construction algorithm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We present a set of programs, DREAM++ (Docking and Reaction programs using Efficient seArch Methods written in C++), for docking computationally generated ligands into macromolecular binding sites. DREAM++ is composed of three programs: ORIENT++, REACT++ and SEARCH++. The program ORIENT++ positions molecules in a binding site with the DOCK algorithm [1, 2]. Its output can be used as input to REACT++ and SEARCH++. The program REACT++ performs user-specified chemical reactions on a docked molecule, so that reaction products can be evaluated for three dimensional complementarity with the macromolecular site. The program SEARCH++ performs an efficient conformation search on the reaction products using a hybrid backtrack [3, 4] and incremental construction [5, 6] algorithm. We have applied the programs to HIV protease–inhibitor complexes as test systems. We found that we can differentiate high-affinity ligands based on several measures: interaction energies, occupancy of protein subsites and the number of successfully docked conformations for each product. Encouraged by the results in the test case, we applied the programs to propose novel inhibitors of HIV protease. These inhibitors can be generated by organic reactions using commercially available reagents. They are alternatives to the inhibitors synthesized by Glaxo [7, 8].
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  • 5
    ISSN: 1573-4951
    Keywords: Molecular similarity ; Database clustering ; Molecular comparison
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary A new formalism for molecular shape description is described. The formalism, based on considering each molecule as a collection of its 3-atom submolecules, is applied to both the graph theory and geometrical coordinate representations of molecules. The timing results for shape description of several databases indicate that this new method is applicable to large databases. Furthermore, results from clustering a small database show good agreement with clustering results obtained by a distance-matching algorithm.
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  • 6
    ISSN: 1573-4951
    Keywords: Molecular recognition ; Ligand binding ; Complementarity ; Hydropathy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Methods that predict geometries of ligands binding to receptor molecules can facilitate ligand discovery and yield information on the factors governing complementarity. Here, the use of atomic hydrophobicities in evaluating binding modes has been examined with four ligand-receptor complexes of known structure. In each system, hundreds of hypothetical binding orientations were generated with DOCK and evaluated using the HINT (Hydropathic INTeractions) exponential function and atomic hydrophobic constants. In three of the four systems, the experimental binding mode received the best HINT score; in the fourth system, the experimental binding mode scored only slightly lower than a similar, apparently reasonable orientation. The HINT function may be generally useful as a scoring method in molecular docking.
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  • 7
    ISSN: 1573-4951
    Keywords: Structure-based design ; Fragment joining ; Ligand design ; Molecular modelling ; Enzyme inhibitors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Significant improvements have been made to the de novo drug design program BUILDER. The BUILDER strategy is to find molecule templates that bind tightly to ‘hot spots’ in the target receptor, and then generate bridges to join these templates. In this paper, the bridging algorithm has been further developed to improve the chemical sense and diversity of the bridges, as well as the robustness of the technique. The improved algorithm is then applied to rebuild known bridges in methotrexate and HIV protease. Finally, the entire BUILDER approach is tested by rebuilding methotrexate de novo.
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  • 8
    ISSN: 1573-4951
    Keywords: Geometric keys ; Molecular descriptors ; Database sereening ; Database clustering ; Pharmacophores
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Distances between key functional groups have been used for some time as molecular descriptors in 3D database screening and clustering calculations. More recently, a number of groups have explored triplets of molecular centers to describe key ligand features in terms of the properties of triangles. Three-body distances are attractive, since they retain more information than pairwise representations. In most applications, the triangular descriptors have been used to detail molecular shape, using all the constituent atoms or molecular surface points as descriptor centers. As a consequence, the database keying times were such that only single conformers could be considered during molecular descriptor calculations. In this paper we reduce the points used in the molecular description down to the key functional centers, as applied in 3D pharmacophore database searches. Molecular triplets can then be calculated which describe the relative dispositions of differing functional groups, made up from multiple molecular conformations of a given molecule. The new triplet descriptors are compared with classical pairwise distance measures using a variety of pharmacophores, and their potential in database screening, clustering and pharmacophore identification is discussed.
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  • 9
    ISSN: 1573-4951
    Keywords: Geometric keys ; Docking ; Molecular similarity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Geometric descriptors are becoming popular tools for encoding molecular shape, for use in database screening and clustering calculations. They provide condensed representations of complex objects and, as a consequence, can usually be compared quite rapidly. Here we present a number of new descriptors and methods for the quantification of molecular shape similarity. The techniques are tested using two different biological systems, with particular emphasis on their potential utility as methods for prescreening shape-based database searches. Results are compared with data sets produced using the DOCK program. We find that such similarity evaluations are useful for finding molecules with complementary shape, and that they contain an enriched number of potential DOCK hits when compared to the original databases. Significant limitations in the utility of such DOCK prescreens are discussed, and potential solutions are considered.
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  • 10
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of the American Chemical Society 88 (1966), S. 3199-3202 
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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