17th March 2010 Work Stream Two
Managing the Wealth of New HTS Data
The Question:Given the large number of molecular structures that have given positive hits in the HTS screens and which are to be release by the pharmaceutical industry (>20,000), to develop systems to:-
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Background:
It is anticipated that by the end of 2010 more than 5 million chemical entities will have been screened for antimalarial activity, based on whole cell screens of P. falciparum malaria. The screens have included fully-synthetic libraries (from both commercial sources and Pharma proprietary libraries) and natural product libraries. Activity has been established based on the ability to stop the growth of asexual P. falciparum malaria parasites over a 24- 48hr exposure period in vitro. The outputs of these screens will be placed into the public domain as indicated in the recent announcement from GSK, one of a number of companies who have submitted their library for screening as part of an initiative driven and financed by the Medicines for Malaria Venture (MMV).
Based on the success rates to date there are likely to be more than 20,000 sub micromolar hits arising from these screens. The malaria genome contains about 5.5K genes of which less than 1% are likely to be druggable targets for chemotherapy. So we must conclude that many of the Hits identified will be targeting the same process. In the coming year or so we expect that the stage specificity of these Hits (i.e. activity against sexual stages and replicating and dormant liver stages) will be established as will their in vitro cellular therapeutic indices based on screens of representative mammalian cell lines.
The Challenge:
The process of taking a screening hit and progressing it through the lead identification, optimisation and candidate selection process is expensive and time consuming. It is questionable if a significant number of these screening Hits can be progressed through this pipeline with current resources without some prioritization. It is unclear at this time what level of detail will be put into the public domain or if anything other than chemical structure will be available to the community. It is unlikely that any organization, including big Pharma, will be able to progress more than a handful of these hits into the development pipeline. It will be important to engage the entire academic community if we are to rationally and efficiently work our way through this wealth of data and turn these Hits into viable drugs for deployment.
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