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  • Springer  (2)
  • Molecular Diversity Preservation International  (1)
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  • 1
    Electronic Resource
    Electronic Resource
    Virtual screening with solvation and ligand-induced complementarity (2000)
    Springer
    Perspectives in drug discovery and design 20 (2000), S. 171-190 
    Details
    ISSN: 1573-9023
    Keywords: bound water ; dihydrofolate reductase ; DNA repairenzymes ; docking ; drug design ; flexibility ; molecularrecognition ; progesterone receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We present our database-screening tool SLIDE, which is capable of screening large data sets of organic compounds for potential ligands to a given binding site of a target protein. Its main feature is the modeling of induced complementarity by making adjustments in the protein side chains and ligand upon binding. Mean-field theory is used to balance the conformational changes in both molecules in order to generate a shape-complementary interface. Solvation is considered by prediction of water molecules likely to be conserved from the crystal structure of the ligand-free protein, and allowing them to mediate ligand interactions, if possible, or including a desolvation penalty when they are displaced by ligand atoms that do not replace the lost hydrogen bonds.A data set of over 175 000 organic molecules was screened for potential ligands to the progesterone receptor, dihydrofolate reductase, and a DNA-repair enzyme. In all cases the screening time was less than a day on a Pentium II processor, and known ligands as well as highly complementary new potential ligands were found.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008737207775
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    RIGIDITY IN GLASSES AND PROTEINS (2000)
    Springer
    Periodica mathematica Hungarica 39 (2000), S. 241-252 
    Details
    ISSN: 1588-2829
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We review recent progress in applying the theory of rigidity to glassy networks and to proteins. These three dimensional systems require a generalization of Laman's theorem, which we have used to develop a technique called the Pebble Game which allows the rigid regions (containing both isostatic and overconstrained parts) and the flexible joints between them, to be found. We show that a flexibility index, which measures the local density of floppy modes, is useful in characterizing the network. A sampling of recent results is given for network glasses, where we show how the glass structure can self-organize to produce an intermediate phase that is stress-free and contains a percolating isostatic cluster. In proteins, we show how maps of the rigid regions and flexible joints, as well as maps of the flexibility index, can help to elucidate the connection between structure and function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1004867612889
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    Paper (German National Licenses)
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  • 3
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    Machine Learning to Identify Flexibility Signatures of Class A GPCR Inhibition (2020)
    Molecular Diversity Preservation International
    Details
    Publication Date: 2020-03-14
    Description: We show that machine learning can pinpoint features distinguishing inactive from active states in proteins, in particular identifying key ligand binding site flexibility transitions in GPCRs that are triggered by biologically active ligands. Our analysis was performed on the helical segments and loops in 18 inactive and 9 active class A G protein-coupled receptors (GPCRs). These three-dimensional (3D) structures were determined in complex with ligands. However, considering the flexible versus rigid state identified by graph-theoretic ProFlex rigidity analysis for each helix and loop segment with the ligand removed, followed by feature selection and k-nearest neighbor classification, was sufficient to identify four segments surrounding the ligand binding site whose flexibility/rigidity accurately predicts whether a GPCR is in an active or inactive state. GPCRs bound to inhibitors were similar in their pattern of flexible versus rigid regions, whereas agonist-bound GPCRs were more flexible and diverse. This new ligand-proximal flexibility signature of GPCR activity was identified without knowledge of the ligand binding mode or previously defined switch regions, while being adjacent to the known transmission switch. Following this proof of concept, the ProFlex flexibility analysis coupled with pattern recognition and activity classification may be useful for predicting whether newly designed ligands behave as activators or inhibitors in protein families in general, based on the pattern of flexibility they induce in the protein.
    Electronic ISSN: 2218-273X
    Topics: Biology
    Published by Molecular Diversity Preservation International
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