L6 Screening and Fragment Based Drug Discovery

What do cell based assays typically test for

Relevant functional outputs like apoptosis, cell proliferation and signalling.

Important features for an assay

-Can it identify if the desired effect is being accomplished by the compound. Positive controls can be used to verify.

-Does it have a good signal window, ensuring a positive result is properly distinguishable from a negative one

-Should be small-scale and automatable as thousands of tests may need to be run.

-If the compound is stored in an organic solvent, the assay need to not be sensitive to the solvent.

Potential issues with assays and their solutions

Fragment-based drug discovery principles

The molecule has weak potency (mM rather than uM) for a lead but has a low molecular weight so is very developable. It importantly has high quality interactions (as it has few interactions they have to be good)

Strategies to further develop fragments

Fragment growing - Enlarge the fragment to form favourable interactions with other regions in the binding site.

Fragment merging - in some cases two fragments could be combined if they interact with separate regions of the binding site and do not overlap except at a point where they could be joined.

Fragment linking - if two fragments bind in different regions you could join them using a linker.