Protein Crystallography in Drug Discovery

Babine, Robert E. / Abdel-Meguid, Sherin S. (Herausgeber)

Methods and Principles in Medicinal Chemistry (Band Nr. 20)

1. Auflage November 2003
XVI, 262 Seiten, Hardcover
131 Abbildungen (41 Farbabbildungen)
11 Tabellen
Monographie

ISBN: 978-3-527-30678-7

Wiley-VCH, Weinheim

Kurzbeschreibung

Researchers from leading pharmaceutical companies present first-hand information, mostly published for the first time. They discuss strategies to derive high-resolution structures for important target protein classes, as well as selected examples of successful protein crystallographic studies. A special section on recent methodological developments is also included.
A valuable companion for crystallographers involved in protein structure determination as well as drug developers pursuing the structure-based approach.

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Der auf Strukturen basierende Entwurf in der Wirkstoffentwicklung hat sich fast überall durchgesetzt. Dementsprechend kommt der Strukturaufklärung wichtiger Zielproteine durch Röntgenkristallographie eine wachsende Bedeutung auch im Pharmabereich zu. Hochaufgelöste Strukturen, die sich zum "rational drug design" einsetzen lassen, stellen einen hohen Wert dar und bilden oft die Basis für ein ganzes Entwicklungsprogramm.
Der Einsatz der Proteinkristallographie zur Wirkstoffentwicklung wird aus unterschiedlichen Blickwinkeln beleuchtet. Neben allgemeinen Strategien für wichtige Klassen von Zielproteinen wie Kinasen oder Proteasen werden konkrete Beispiele der aus der aktuellen Wirkstoffentwicklung beschrieben. Die Berichte stammen durchweg von den an der Entwicklung selbst beteiligten Forschern und bieten Informationen aus erster Hand, die hier erstmals veröffentlicht werden. Abschließend werden neueste technische Entwicklungen der Kristallographie vorgestellt, wie etwa die Entwicklung von Hochdurchsatzsystemen.
Mit seinem durchgehenden Praxisbezug wendet sich dieses Buch an alle Kristallographen, die Proteinstrukturen aufklären wollen und bietet eine wertvolle Grundlage für Anwender des strukturbasierten Wirkstoffdesigns.

Molecular Recognition of Nuclear Hormone Receptor-Ligand Complexes
Kinases
The Proteasome as a Drug Target
Antibiotics and the Ribosome
Strucutre-based Design of Cathepsin K Inhibitors
Structure-based Design of Potent and Selective Cdk4 Inhibitors
Crystallization and Analysis of Serine Proteases with Ecotin
X-ray Crystallography in the Development of Orthogonal Ligand-Receptor Pairs
Engineering Proteins to Promote Crystallization
High-throughput Crystallography
Micro-crystallization

"Medicinal chemists will find the book invaluable whether they are working in an area of one of the chapters or wish to apply the methods described to other projects. Structural and computational biologists should also find it useful and thought-provoking."
ChemBioChem August

Lars-Oliver Essen, Fachbereich Chemie, Philipps-Universität Marburg, Angewandte Chemie, 3. Dezemberheft 2004-116/47 und Angewandte Chemie International Edition, 3rd December Issue 2004-43/47

"The quality of the individual chapters of this volume is high, and each of the contributors is to be commended for their efforts."

Steven W. Muchmore, Department of Structural Biology, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, Illinois, Journal of Medicinal Chemistry, Vol. 47, No. 26, 2004

"... an important contribution to pharmaceutical research and development."
American Journal of Therapeutics

Robert E. Babine has diverse drug discovery experience over the past 20 years and is presently the Director of Structural & Computational Chemistry at SPRL in Cambridge, Massachusetts. After receiving his Ph.D. in synthetic organic chemistry at Brown University he joined the medicinal chemistry group at Lederle Laboratories. During his 10 years at Lederle his research evolved into structure-based drug design, culminating in a project that discovered hydroxylaminepentanamide HIV protease inhibitors. Thereafter, he was in the medicinal chemistry group at Agouron Pharmaceuticals where he was involved in the early phase discovery of rhinovirus 3C protease inhibitors. After a 2-year stay at Eli Lilly he joined the new startup company SPRL in 2000.
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Sherin S. Abdel-Meguid is Chief Scientific Officer and Founder of Suntory Pharmaceutical Research Laboratories (SPRL), a structure-based drug discovery company located in Cambridge, Massachusetts. He joined SPRL from SmithKline Beecham (SB) where he was Director of Macromolecular Sciences and Structural Biology, and director of the IL18, Herpes virus protease and CD28 programs. Prior to his work for SB, he was Head of Biophysical Sciences and Protein Engineering at Monsanto. At Monsanto, he built one of the first macromolecular crystallography groups in the pharmaceutical industry. He holds a Ph.D. in Physical Chemistry and M.S. and B.S. degrees in Biochemistry.

R. E. Babine, Suntory Research Laboratories, Cambridge, MA; S. S. Abdel-Meguid, Suntory Research Laboratories, Cambridge, MA