Cole Black Kenneth New Unlisted York Profiling
Chapter 9) within large compound libraries. The decision as to whether a particular hit is worth pursuing as a chemical lead in a drug discovery project depends on several factors, important ones being its chemical characteristics and its pharmacodynamic and pharmacokinetic properties. These aspects, broadly covered by the term ‘compound profiling’, are discussed in detail in the next three chapters.
The technology involved in miniaturization, automation and assay readouts required for HTS has developed rapidly and continues to do so. As this technology evolves, the laboratory set-ups installed in HTS facilities are steadily broadening their capabilities beyond their primary function of identifying hits to apply HTS techniques to more diverse compound profiling assays relating not only to the target selectivity of compound libraries, but also to their pharmacokinetic characteristics. Increasingly, therefore, early compound profiling tasks on ‘hit’ compounds are being carried out in HTS laboratories where the necessary technological expertise is concentrated. Such assays are also very helpful in the ‘lead identification’ stage of a project, where focused synthetic compound libraries based on the initial hits need to be assessed. As this work generally involves testing small compound libraries, usually fewer than 1000 compounds at a time, in several different assays, small dedicated robotic workstations are needed, rather than the fast but inflexible factory-style robotic assemblies used for large-scale HTS.
In vitro pharmacokinetic assays (see Chapter 10), which are not generally project specific and can be automated to run in medium-throughput fashion, are very suitable for running in this environment. This extension of the work of HTS laboratories beyond the primary task of finding hits is a clear and continuing trend, for which the term ‘high-throughput profiling’ (HTP) has been coined. It brings the work of HTS laboratories into a close and healthy relationship with drug discovery teams. The highly disciplined approach to assay formats and data logging that is essential for HTS, but not second nature to many laboratory scientists, brings the advantage that profiling data collected over a wide range of projects and drug targets is logged in standard database formats, and is therefore a valuable company-wide tool for analysing structure–activity relationships. This necessity to handle and visualize such data has driven the development software packages such as Spotfire (spotfire.tibco.com).
In summary, it is clear that pharmacological profiling will be an increasing activity of HTS units in the future, and will help to add further value in the drug discovery chain.