Title:
LIGAND SCREENING AND DESIGN BY X-RAY CRYSTALLOGRAPHY
Document Type and Number:
WIPO Patent Application WO1999045379
Kind Code:
A3
Abstract:
X-ray crystallography can be used to screen compounds that are not known ligands of a target biomolecule for their ability to bind the target biomolecule. The method includes obtaining a crystal of a target biomolecule; exposing the target biomolecule crytal to one or more test samples; and obtaining an X-ray crystal diffraction pattern to determine whether a ligand/receptor complex is formed. The target is exposed to the test samples by either co-crystallizing a biomolecule in the presence of one or more test samples or soaking the biomolecule crystal in a solution of one or more test samples. In another embodiment, structural information from ligand/receptor complexes are used to design ligands that bind tighter, that bind more specifically, that have better biological activity or that have better safety profile. A further embodiment of the invention comprises identifying or designing biologically-active moieties by the instant process. In a further embodiment, a biomolecule crystal having an easily accessible active site is formed by co-crystallizing the biomolecule with a degradable ligand and degrading the ligand.
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Inventors:
NIENABER VICKI L
GREER JONATHAN
ABAD-ZAPATERO CELERINO
NORBECK DANIEL W
GREER JONATHAN
ABAD-ZAPATERO CELERINO
NORBECK DANIEL W
Application Number:
PCT/US1999/004967
Publication Date:
November 25, 1999
Filing Date:
March 05, 1999
Export Citation:
Assignee:
ABBOTT LAB (US)
International Classes:
G01N23/20; G01N33/15; G01N33/50; G01N33/53; G01N33/68; (IPC1-7): G01N33/53; C30B7/00
Other References:
GREER, JONATHAN ET AL: "Application of the Three-Dimensional Structures of Protein Target Molecules in Structure-Based Drug Design", J. MED. CHEM. (1994), 37(8), 1035-54, XP002116744
NIENABER, VICKI L. ET AL: "A Noncleavable Retro-Binding Peptide That Spans the Substrate Binding Cleft of Serine Proteases. Atomic Structure of Nazumamide A: Human Thrombin", J. AM. CHEM. SOC. (1996), 118(29), 6807-6810, XP002116745
VERLINDE, C. ET AL.: "Structure-based drug design: progress, results and challenges", STRUCTURE, vol. 2, no. 7, 15 July 1994 (1994-07-15), pages 577 - 587, XP002117026
VERLINDE, C. ET AL.: "In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach", JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. 6, no. 1, February 1992 (1992-02-01), pages 131 - 147, XP002117027
NIENABER, VICKI L. ET AL: "A Noncleavable Retro-Binding Peptide That Spans the Substrate Binding Cleft of Serine Proteases. Atomic Structure of Nazumamide A: Human Thrombin", J. AM. CHEM. SOC. (1996), 118(29), 6807-6810, XP002116745
VERLINDE, C. ET AL.: "Structure-based drug design: progress, results and challenges", STRUCTURE, vol. 2, no. 7, 15 July 1994 (1994-07-15), pages 577 - 587, XP002117026
VERLINDE, C. ET AL.: "In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach", JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. 6, no. 1, February 1992 (1992-02-01), pages 131 - 147, XP002117027
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