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What is Crystallographic Screening and Why is it Making a Comeback?

What is Crystallographic Screening?

Crystallographic screening is a method used to detect ligands that bind to a target protein. What makes this metod special is that it also provides structural data about the binding location and interactions between the ligand and protein. The crystal itself has the protein molecules lined up in an ordered array with large solvent channels so that ligands can soak in and bind to sites on the crystallized protein. This method is exceptionally successful in detecting weakly binding ligands because the protein is highly concentrated in the crystal. Once the crystal has been soaked in the cocktail of ligands, diffraction data are collected and used to calculate an electron density map to determine if any of the ligands bound to the protein. If they do bind, one can tell by a visible positive electron density peak in a difference density map between the putative ligand protein complex and apoprotein. The ligand cocktails should be designed so that each ligand has a visibly different shape (shape-diverse mixture), so when the electron density map is obtained, one can determine which particular ligand has bound to the protein from the cocktail. (Nienaber et. al 2000). Having the crystal structure of a protein or ligand helps one determine which fragments will be useful to move into fragment-to-lead optimization.

Why is it making a comeback?

Though it was considered to provide useful information, the popularity of crystallographic screening has waxed and waned over the past few decades. When first introduced, it was one of the few methods that could reliably detect weakly binding ligands. However, limitations on x-ray beamtime and robotics led to additional methods such as SPR, NMR and Tm shift assays as pre-screens. Current advances in robotic and crystallization technology and software tools have greatly simplified the screening method. Furthermore, the transition from pre-screens to crystal structure is more labor intensive than originally envisioned. The combination of these factors has led to a resurgence in crystallographic screening based upon the original premise that it permits detection of the binding event and provides a picture of ligand binding site and interactions in a single step. Without crystallographic screening, one is unable to obtain a such structural data, which again, is tremendously useful in process and fragment optimization. In response to the resurgence in crystallographic screening, Zenobia has developed new versions of the ZEN-CORE 288(TM) optimized particularly for crystallographic screening. These plates give you the option to do crystallographic screens with individual fragments, shape-diverse mixtures/cocktails of 3, or shape-diverse mixtures/cocktails of 6 and can be custom-plated into the plate of your choice.

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Nienaber, Vicki et. al (2000). Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat Biotechnol. 2000 Oct;18(10):1105-8.

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