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Drug Discovery

approach will enable the delivery of key structure activity relationship data in a timescale of hours rather than weeks or months.

Assays need not be limited just to biology, options exist to enable the determination of key physicochemical parameters, for example logD which will ensure molecules have not only the required biological profile but also measured prop- erties to significantly increase their potential as future drugs.

Although the overall logic of the above argu- ments is hard to refute, a number of key challenges to achieve this level of integration and automation still remain. It is now believed that most technical hurdles can be resolved by the integration and adaption of existing technologies, in part through the exploitation of engineering and software expertise coupled with a pragmatic approach to technology R&D.

The flow paradigm now available for both syn- thesis and screening enables an overall platform approach whereby the small molecule is continu- ously processed through a series of connected flu- idic processes. This requires a well thought through specification coupled with considerable knowledge and experience in the integration and engineering, particularly flow control of microflu- idics, where the quality and control of the varied pumping requirements are key to success. While this may be trivialised to just some plumbing it remains without doubt a significant challenge for the integration.

Key to the generation of robust medicinal chem- istry data is knowing that you have the right mate- rial, it is of high purity and known concentration. Fortunately modern HPLC systems now enable rapid purification and analysis with molecular structure confirmation by mass spectrometry. The amount of material is more challenging as simple UV methods are not quantitative, however, evapo- rative light scattering detection does now provide good levels of quantification provided the appro- priate calibration methods are utilised. An interesting difference between the chemical synthesis world and that of biological assay is the concentrations typically used. Flow synthesis, where reagents are typically at concentrations of low millimolar is still considerably in excess of those required in a typical biological assay. A high dynamic range dilution technique is consequently essential to make this connection. While simple methods can enable dilution ratios of 200-fold, an innovative approach was required to achieve the three orders of magnitude likely to be required to enable the full integration. Although a technical

Drug Discovery World Summer 2011

challenge, this approach does offer the advantage of diluting down any organics post-purification that may interfere with the assay. Indeed even the 200-fold dilution would mean a maximum organ- ic concentration of 0.5% and in practice could be considerably lower than this.

Control of a range of different hardware com- ponents, even within a well defined process, is not a trivial exercise. The various components require integration and ideally should avoid the rewriting of existing component control software. A number of commercial solutions exist for the integration of laboratory hardware which enable the integration approach where the focus can be maintained on platform control and scheduling rather than the recreation of existing control software. Instrument providers can facilitate this through the provision of simple options for external hardware control and the ability to readily access data generated. An integrated platform generates a wide range of data, both the experimental parameters for the molecules prepared (the laboratory notebook ele- ment) alongside the chemical analysis and biologi- cal assay data. There is a clear requirement for an integral informatics database that can readily cap- ture, store and retrieve all the data associated with a particular experiment. This then provides the all- important structure activity data alongside the experimental methods to enable reproducing the results, both key to ensuring that the data will sup- port intellectual property prevention. Computational methods for the selection of mol- ecules for drug discovery are constantly evolving and methods are now available that can assist the

Precision adjustment is required for alignment when working on the microfluidic scale


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