Crystallography Research Today is a free monthly online journal that collates and summarizes the latest research about Crystallography, including details on x-ray crystals, techniques, analyses, structures.

Automated protein-ligand crystallography for structure-based drug design.

Mooij WT, Hartshorn MJ, Tickle IJ, Sharff AJ, Verdonk ML, Jhoti H

Astex Therapeutics Ltd., 436 Cambridge Science Park, Cambridge CB4 0QA, UK.

An approach to automate protein-ligand crystallography is presented, with the aim of increasing the number of structures available to structure-based drug design. The methods we propose deal with the automatic interpretation of diffraction data for targets with known protein structures, and provide easy access to the results. Central to the system is a novel procedure that fully automates the placement of ligands into electron density maps. Automation provides an objective way to structure solution, whereas manual placement can be rather subjective, especially for data of low to medium resolution. Ligands are placed by docking into electron density, whilst taking care of protein-ligand interactions. The ligand fitting procedure has been validated on both public domain and in-house examples. Some of the latter deal with cocktails of low-molecular weight compounds, as used in fragment-based drug discovery by crystallography. For such library-screening experiments we show that the method can automatically identify which of the compounds from a cocktail is bound.

Published 11 August 2006 in ChemMedChem, 1(8): 827-38.
Full-text of this article is available online (may require subscription).

© 2005-2008 Crystallography Research Today. All Rights Reserved.