A variety of approaches are available for the identification of chemical start points for drug discovery projects. These include screening of large collections of small molecules (chemical libraries of up to 2 million members are available in some research organisations) in an automated manner. Alternatively knowledge of the target (or closely related targets) can be used to design inhibitors in silico or select focused sets of compounds displaying complimentary shapes and properties for screening. A newer approach, focusing on much smaller molecules than would have been previously considered for hit ID, is also being used at Sussex. These ‘drug fragments’ are screened for weak interactions with the target protein using sensitive biophysical 
techniques to identify otherwise undetectable binding. Combining this information with structural knowledge of the binding site allows rapid optimisation of such compounds with accompanying improved drug-like properties.
Verification of active compounds identified through any screening approach is an important part of the drug discovery process. Through a rigorous evaluation of potential hits the most promising compounds are selected to progress to Hits to Leads programs.
This selection process includes:
- Exclusion of hits with potential reactivity or assay interference
- Re-synthesis and confirmation of structure
- Re-testing and confirmation of on-target activity
- Assessment of drug-like properties using computational analysis and early physicochemical and ADME measurements
- Assessment of patent potential
- Structure-activity relationship (SAR) evaluation
- Ranking of hits or hit series to select the most promising for the hit-to-lead phase
