Drug Discovery
to support the medicinal chemist in the identifica- tion of new drug molecules. The delivery of SAR data to the medicinal chemist, on a regular and frequent basis will enable such individuals to focus much more on molecular design, the key area where both a wide range of project experience combine with innovation to influence the design process and more rapidly deliver candidate quali- ty molecules.
The fast iteration also provides opportunities for the identification of potent tool molecules to probe target tractability and mechanism of action. This offers significant scope for impacting on early stage discovery biology where research efforts may be hampered by inadequate tools to elucidate the biology.
Accurate control of pumping and switching is key to
working with low flow rates in microfluidics
medicinal chemist in proposing compounds for synthesis. These methods may be based upon sim- ple calculated properties, for example the so called ‘Rule of 5’8 to ensure experiments stay within rel- evant areas of chemical space as well as existing structure activity relationships and knowledge of the biological target. There are now a number of software tools which enable the sequential manip- ulation of data9,10, the so called data pipelining approach (which the authors particularly like due to the similarity of the data manipulation approach to the continuous pipeline which facilitates the experimental data generation in the first place). Will such a platform be able to identify candi- date molecules just through loading up of reagents and initiating the process? The short answer is no, the philosophy behind the integrated make and screen paradigm is enabling the generation of data
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Following up on hit finding campaigns will take on a new dimension. Currently, any one of a num- ber of hit identification methods may identify a good number of interesting looking molecules which then go through a rigorous paper-based triage process to ensure only the most tractable are actually resourced in the laboratory. Given the high overheads of generation of SAR, even in the current paradigm of outsourced synthesis, this makes per- fect sense, however once you have the ability to rap- idly explore initial SAR in a matter of days or just a few weeks this becomes less sensible. Evaluation of a wider range of chemical hits, coupled with stringent design criteria, will enable a more thor- ough evaluation of the accessible chemical space which would be expected to impact positively on the final quality of candidates being produced. A key element of the fully integrated approach is the rapid cycle time. Medicinal chemistry is the iterative generation of structure activity relation- ships and one might expect that the ultimate qual- ity of molecules generated would, in part, be a function of the number of iterations. Beyond a cer- tain point the speed of iteration will be dictated by the biological assay, particularly in advanced lead optimisation where the biological assay may include complex cell-based and in vivo data gener- ation which inherently take long periods of time to complete. The generation of better quality mole- cules ahead of this time, through an increased number of iterations (in a significantly shorter peri- od of time) will impact positively on quality. What length of cycle time might ultimately be achieved? At present the integration of a straight- forward two-step chemical synthesis with a simple biochemical assay would be expected within a two- hour window. This translates to up to 12 cycles in a 24-hour period. Looking just a little further for- ward, improved optimisation of chemistry and
Drug Discovery World Summer 2011
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