LIGAND SCREENING AND DESIGN BY X-RAY CRYSTALLOGRAPHY

摘要

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 crystal 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.