Lead optimisation projects progress by making successive enhancements to one or more starting structures. This is a classic multi-objective optimisation procedure where the goal is not only to improve potency but also to improve physicochemical and ADME properties.
Genomics activity has been criticised for having elucidated a plethora of potentially interesting drug targets, each awaiting further validation, but having not yet revolutionised the pharmaceutical industry or replaced traditional drug discovery pipelines. Here, we detail applications for improving target selectivity of known therapeutic molecules to known targets by employing technologies not previously accessible to the pharmaceutical industry, ie appropriatelydesigned protein biochips. Protein micro-arrays can be used to screen lead molecules (antibodies, protein biomolecules and small molecule drugs), and iterations thereof, for the most specific target binders prior to toxicological, pre-clinical and clinical testing. Improvements in target selectivity linked to optimised recognition profiles following exposure to millions of potential binding sites derived from the human genome should translate into reduced adverse drug effects and shorter times to registration.
The coupling of High Throughput co-structure analysis with focused library generation is not only proving a powerful general tool in lead optimisation but also increasing the probability of successful discovery of high quality oral development compounds for targets that have been quite difficult for the pharmaceutical industry.