XChem: X-ray structure-accelerated, synthesis-aligned fragment medicinal chemistry
Fragment based drug discovery is a well-established method widely used by pharmaceutical & biotech companies and has more recently adopted by a few academic groups. The process is applied to identify low molecular weight compounds binding weakly to a target (Kd uM to mM range). Because of the molecules’ size, a comprehensive screen can be achieved using a rather small library of well diversified compounds. With a few molecules already marketed or at various clinical stages, the process has clearly demonstrated its effectiveness and pertinence.
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Echo 550: acoustic liquid dispenser
I04-1: Powerful x-ray source (3rd generation synchrotron), fully automated beamline, fast and high capacity sample changer (up to x pucks/y samples), fast readout detector Pilatus P6M (25hz). More information here
Auto-processing pipeline: Building on Diamond’s pipeline to process data via Xia2 and provide ready to use difference maps through Dimple. More information here
• Core set of Ro3 library from May bridge (~900 compounds). More information here
• SGC library designed for compatibility with X-ray crystallography and rapid chemistry
• Screen up to 500 samples a day
• Screen singletons, no hit deconvolution required
• Obtain a direct structural feedback on your screening campaign, reducing significantly the chance of false positives
• Hit rate comparable to the ones from other methods (1-10%)
• Rapid turnover between projects
• Compatible with external libraries.
• A reproducible and robust crystal system
• A well diffracting crystal system (<2.5A resolution to properly assign extra electron density)
• Crystals produced/producible in SwissCi 3 wells crystallisation tray format (other format available soon)
• The pdb model(s) and cell parameters related to the crystal system of interest
• For external library, compounds concentration >100mM in DMSO
Crystallographic fragment screening is a powerful process to determine low molecular weight compounds binding weakly to a drug target (from um to mM Kd). The method provides direct structural information about the ligand-target interactions, at atomic level, on which chemical chemists can rely on to develop new/potential potent leads.
What can it tell me?
• Discriminate positive hits, i.e. compound binding to the target
• Determine molecular interaction between hits and the target
• Highlight conformational changes of the target which would be intractable with other methods
• Presence of new binding site(s) and allosteric site(s)
What does the data looks like?
• Raw data are X-ray diffraction images from the different samples
• Processed data provides electron density map and atom coordinates for the model of the target
• Positive difference density peaks might highlight a bound ligand (and or some conformational changes of the target)
• Majority of case often difference map look like “apo” form (i.e. no compound is bound). Typical hit 1-10%, comparable with other biophysical screening methods
• A robust and reproducible crystal system
• A crystal system diffracting to <2.5A, otherwise the ligand’s orientation would be too difficult to determine
• Crystals produced in SwissCi 3 drops HTX crystallisation tray format (more format to come)
• The PDB model(s) and cell parameters related to the crystal system
• For external libraries, high compound concentration (>100 mM in DMSO, in plate format compatible with the Echo 550)
• Small libraries of compounds provide comprehensive screening options
• Rapid turnover between projects
• Direct structural feedback about the molecular interactions between the hit and the target
• Rapid sample generation
• Fully automated data collection and data processing
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