News > Fragment Based Lead Discovery 2010
October 10, 2010
Selcia are attending the FBDL 2010 conference in Philadelpia USA from 10-13 October 2010 and are presenting posters on fragment screening using capillary electrophoresis and the Selcia fragment library.
Selcia are attending this year's Fragment Based Lead Discovery conference in Philadelphia, Pennsylvania, USA from 10 to 13 October 2010. Our delegates will be pleased to meet you there and discuss our science, capabilities and service offering in fragment screening and drug discovery.
For more information on the event please go to the FBLD website.
Selcia will be presenting the following posters:
1) CEfrag Screen: Fragment Screening Using Capillary Electrophoresis – an Innovative and Useful Tool for the Fragment Screening Tool Box
2) The Selcia Fragment Library: Design, Analysis and Quality Control
Abstracts
1) CEfrag Screen: Fragment Screening Using Capillary Electrophoresis – an Innovative and Useful Tool for the Fragment Screening Tool Box
Dallas Hughes2, Carol Austin1, Leonid Raskovetsky2, Sharon Magnolo2, Yuriy Dunayevskiy2, Jonathan Sanvoisin1, Martin Walker1, Simon Pettit1, Clive L. Cornell1.
1Discovery, Selcia Ltd, Fyfield Business and Research Park, Ongar, CM5 0GS, UK
2Selcia US Inc., 842 Upper Union St. #3, Franklin, MA 0203, USA
CEfrag is a novel proprietary technique for fragment-based screening that uses high resolution capillary electrophoresis (CE). The technique is a microscale binding assay ideally suited for detecting weak binding interactions between fragments and protein targets. The principle of the technique uses CE to detect a reduction in the interaction of a probe ligand with its target protein in the presence of a binding fragment. The competitive nature of this interaction ensures that fragment “hits” bind in a defined manner and avoids the problem of false positives caused by non-specific binding. The technique is broadly applicable to a wide range of targets with low consumption of protein and other reagents. There is no need to immobilise or modify the target protein. IC50s can be generated for active compounds, and have shown to correlate well with orthogonal techniques. In addition, the CEfragTM screen can be adapted to screen for fragments and other compounds that modulate protein-protein and protein-nucleic acid interactions.
Several examples of the method will be presented, including case studies of our proprietary fragment library screened against several targets. Evaluation of CEfragTM primary hit compounds, including confirmation of hit activity in secondary functional and binding assays, will be shown.
2) The Selcia Fragment Library: Design, Analysis and Quality Control
Carol Austin1, Simon Pettit1, David Scowen1, Jussi Kangasmetsa1, Andrew J. Keats1, Chris Swain2, Lauren Freeman3, Bob Carling1, Ian R. Marshall1, David O’Brien1, Mike Jones1, Martin Walker1, Clive L. Cornell1.
1Discovery Division, Selcia Ltd., Fyfield Business and Research Park, Ongar, Essex, CM5 0GS, UK
2Cambridge MedChem Consulting Ltd., http://www.cambridgemedchemconsulting.com, UK
3University of Bath, Bath, BA2 7AY, UK
The Selcia Fragment Library was designed to be generic and compatible with our proprietary CEfragTM screen, a novel fragment screening technique based on capillary electrophoresis. The library, currently ~1300 compounds was designed by Selcia’s medicinal chemists to ‘rule-of-3’ criteria and consists of a combination of commercial and unique non-commercial compounds. Each compound was selected for chemical attractiveness and expandability (i.e. availability of near neighbours). During the design of the library, close attention was made to quality control; compounds that were either potentially reactive or predicted to be poorly soluble (i.e. calc sol <3 mM) were excluded. In addition, solubility was also measured after dilution in buffer, similar to the CEfragTM screening conditions; ~3% of the library was excluded based on the solubility results. All compounds in the library were further subjected to detailed quality control, using LC/MS and 1H-NMR (500MHz); those that did not meet the storage purity criteria (>95% after 3 months in DMSO solution at -80C) were excluded. The Selcia Fragment Library was compared with 8 commercially available fragment libraries and little overlap was observed (<13%). In addition, it has been shown that greater than 20% of the fragments are substructures within known marketed drugs. Using a Tanimoto similarity coefficient of 0.9, cluster analysis demonstrated that the majority of compounds are singletons, indicating the chemical diversity of the Selcia Fragment Library.