Drug Discovery
Keeping ahead of the flow
Can the next generation of flow chemistry and biology platforms be fully integrated to transform the efficiency of small-molecule drug discovery for pharmaceutical industry?
There have been many false dawns in small-molecule drug discovery, promising individual technologies and integrated platforms to improve the efficiency of drug discovery. Although high-throughput screening, combinatorial chemistry and computational methods have all led to the rapid expansion of novel hit molecules and target-focused libraries, conventional medicinal chemistry is still the most effective way to optimise those early hits into the development compounds that can become drugs. This lengthy optimisation process is increasingly being outsourced to various locations worldwide with lower overheads and reduced long-term liabilities, as there has been no other expedient alternative to driving down costs to improve the earnings of pharmaceutical companies in the short term. However, effective integration and intelligent automation of the next generation of flow chemistry and biology technologies now has the real potential to transform this iterative process by enabling a step change in the efficiency, as well as a radical shortening of the timescales required to discover a candidate compound ready for development. It is envisaged by the authors that new small molecule integrated technology platforms will become sufficiently disruptive to challenge the efficiency of the latest monoclonal antibody discovery platforms.
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mall-molecule drug discovery involves an iterative process of molecular design, chemi- cal synthesis, biological assay and data analy- sis feeding directly into the next cycle. A typical medicinal chemistry project might encompass mul- tiple cycles before a candidate compound is ready for development or the project is aborted. In par- ticular, a complex range of assays are required to assess the potency and selectivity of a new mole- cule at the target of interest, as well as to assess in vitro the way the human body would deal with and respond to that molecule in vivo (eg metabolism and toxicity). Furthermore, the physical properties of the molecule, which will impact on the ease of
Drug Discovery World Summer 2011
formulation of an eventual therapeutic, need to be taken into account. This iterative process takes time, involves the interaction of different multidis- ciplinary teams and it may be many weeks after the first synthesis of a molecule before a more com- plete picture of the biological and physical proper- ties can be built, inevitably leading to the synthesis of molecules that retrospectively are of limited value. This process typically takes from a year to a decade, depending on the chemical starting point and degree of biological optimisation required, and involves at least one or more teams of skilled medicinal chemists.
The discovery process for small molecules 25
By Dr J Mark Treherne, Dr David M Parry and Christopher N Selway
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