Aufsatz
Anwendung und Grenzen kristallographischer Daten im strukturbezogenen Liganden- und Wirkstoff-Design
Andrew M. Davis Dr.,
Simon J. Teague Dr.,
Gerard J. Kleywegt Dr.,
Andrew M. Davis Dr.
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (Großbritannien), Fax: (+44) 150-964-5576
Search for more papers by this authorSimon J. Teague Dr.
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (Großbritannien), Fax: (+44) 150-964-5576
Search for more papers by this authorGerard J. Kleywegt Dr.
Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre, Box 596, SE-751 24 Uppsala, Schweden
Search for more papers by this authorAndrew M. Davis Dr.,
Simon J. Teague Dr.,
Gerard J. Kleywegt Dr.,
Andrew M. Davis Dr.
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (Großbritannien), Fax: (+44) 150-964-5576
Search for more papers by this authorSimon J. Teague Dr.
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (Großbritannien), Fax: (+44) 150-964-5576
Search for more papers by this authorGerard J. Kleywegt Dr.
Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre, Box 596, SE-751 24 Uppsala, Schweden
Search for more papers by this authorAbstract
Strukturbezogenes Design konzentriert sich auf die Optimierung der Ligandenaffinität, aber ein erfolgreiches Wirkstoff-Design erfordert auch die Optimierung anderer Eigenschaften. Die Informationen zur Protein-Ligand-Struktur stammen meist aus der Kristallstrukturanalyse. Unsicherheiten, die während der Entwicklung eines Atommodells aus der experimentell erhaltenen Elektronendichte eingeführt werden, lassen sich manchmal nur eingeschränkt beurteilen. Ungenauigkeiten im Atommodell können aber erhebliche Konsequenzen haben, wenn das Modell anschließend als Grundlage für manuelles Design, Docking- und Scoring-Rechnungen und virtuelles Screening dient. Manche Ansätze im strukturbezogenen Design nutzen inzwischen das Durchmustern von Substanzbibliotheken mit NMR-spektroskopischen und röntgenographischen Methoden, um kleine polare Template zu identifizieren und anschließend zu optimieren. Nach diesen leitstrukturähnlichen Verbindungen wird auch mit dem moderneren Hochdurchsatz-Screening gesucht.
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