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Reducing the PAINS in High Throughput Screening: Assay design as a tool for maximising efficiency

Reducing the PAINS in High Throughput Screening: Assay design as a tool for maximising efficiency

By Dr Philip S. Jones and Dr Stuart P. McElroy

While the quality of the compound collection is frequently described as a key determinant of the success of a high throughput screening campaign, in our opinion equally important is the design and execution of the primary assay and the subsequent confirmatory screens used to establish the authenticity of the hits that are discovered.

This article will describe, with examples, how understanding the likely mechanisms of false positives in advance of screening informs the design of the hit triage, thus increasing the likelihood of discovering optimisable chemical matter and avoiding costly wasting of resource. We describe the use of a bespoke ‘Robustness Set’ of nuisance compounds and how it can be used in conjunction with adjusting the conditions of the assay. We also present an example where hit identification was initially confounded by the presence of a common pharmaceutically-acceptable salt and will describe how biophysical data was used to characterise the interactions and triage of the hits.

The small-molecule drug discovery ecosystem has changed enormously over the past two decades (1). Currently only two of the top 10 best-selling medicines are small molecules, whereas 15-years ago all 10 were in this category (2). While, of course, other statistics are arguably more important, such as the number of patients treated, this change has led to challenges in funding smallmolecule programmes in many discovery organisations including major pharma, for example: “There was a view that vaccines, antibodies and other biopharmaceuticals were more profitable than small-molecule drugs, in part because competitors were not as adept at bringing generic versions to market.” (3) There has been a shift to new modalities in discovery (4) and some notable successes have been scored in the clinic with significant promise of future advances. At the organisational level there have been very significant reductions in staffing in pharma companies, in particular in discovery R&D (5), which has mirrored the growth in open innovation models where the search for innovation relies on increasing interactions with academic groups and biotech (6). These structural changes in the drug discovery landscape have led to the rise of the ‘virtual biotech’, where a nucleus of individuals, typically a combination of disease specialists and ex-pharma project managers backed by private investment, access all of the requisite discovery and development infrastructure via outsourcing to CROs (7). However, these small or micro organisations, often originating from academia, inevitably have gaps in their capacities, capabilities and/or institutional knowledge base and one area where this is evident is in high throughput screening (HTS)....

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