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  • 1
    Electronic Resource
    Electronic Resource
    Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach (2000)
    Springer
    Journal of computer aided molecular design 14 (2000), S. 161-179 
    Details
    ISSN: 1573-4951
    Keywords: de novo design ; finite-difference Poisson–Boltzmann ; HIV-1 aspartic proteinase ; inhibitors of dimerization ; MCSS ; structure-based drug design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Inhibition of dimerization to the active form of the HIV-1 aspartic proteinase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) methodology was used to generate functionality maps for the dimerization interface of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, once postprocessed to take into account solvation effects, are in good agreement with experimental data on peptides that bind to the interface. The MCSS minima combined with an approach for computational combinatorial ligand design yielded a set of modified HIV-1 PR C-terminal peptides that are similar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008146201260
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  • 2
    Electronic Resource
    Electronic Resource
    Functionality maps of binding sites: A multiple copy simultaneous search method (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 29-34 
    Details
    ISSN: 0887-3585
    Keywords: drug-design ; ligand-binding ; hemagglutinin ; functional groups ; MCSS ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A new method is proposed for determining energetically favorable positions and orientations for functional groups on the surface of proteins with known three-dimensional structure. From 1,000 to 5,000 copies of a functional group are randomly placed in the site and subjected to simultaneous energy minimization and/or quenched molecular dynamics. The resulting functionality maps of a protein receptor site, which can take account of its flexibility, can be used for the analysis of protein ligand interactions and rational drug design. Application of the method to the sialic acid binding site of the influenza coat protein, hemagglutinin, yields functional group minima that correspond with those of the ligand in a cocrystal structure.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110104
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  • 3
    Electronic Resource
    Electronic Resource
    An automated method for dynamic ligand design (1995)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 23 (1995), S. 472-490 
    Details
    ISSN: 0887-3585
    Keywords: drug design ; FKBP ; FK506 ; immunophilin ; MCSS ; DLD ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: An automated method for the dynamic ligand design (DLD) for a binding site of known structure is described. The method can be used for the creation of de novo ligands and for the modification of existing ligands. The binding site is saturated with atoms (sp3 carbon atoms in the present implementation) that form molecules under the influence of a potential function that joins atoms to each other with the correct stereochemistry. The resulting molecules are linked to precomputed functional group minimum energy positions in the binding site. The generalized potential function allows atoms to sample a continuous parameter space that includes the Cartesian coordinates and their occupancy and type, e.g., the method allows change of an sp3 carbon into an sp2 carbon or oxygen. A parameter space formulated in this way can then be sampled and optimized by a variety of methods. In this work, molecules are generated by use of a Monte Carlo simulated annealing algorithm. The DLD method is illustrated by its application to the binding site of FK506 binding protein (FKBP), an immunophilin. De novo ligands are designed and modification of the immunosuppressant drug FK506 are suggested. The results demonstrate that the dynamic ligand design approach can automatically construct ligands which complement both the shape and charge distribution of the binding site. © 1995 Wiley-Liss, Inc.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340230403
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    Paper (German National Licenses)
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