Drug discovery institute identifies Huntington's leads

BioAscent Discovery unique on-demand compound library, Compound Cloud, has been used by the Alborada Drug Discovery Institute for virtual screening and to progress promising leads against a novel Huntington's disease target.

 The Alborada Drug Discovery Institute, established by Alzheimer's Research UK, is developing new approaches to slow or halt the progress of the diseases that cause dementia. The Institute's primary focus is to explore mechanisms associated with the misfolded, aggregated proteins which characterise most neurodegenerative diseases.
The Institute has an advanced drug discovery programme seeking to develop inhibitors of the PI5P4 kinases. Lead Academic Scientist Professor David Rubinsztein has previously used genetic studies to show that blocking these enzymes upregulates autophagy, a natural cellular protein clearance mechanism which is capable of digesting and removing neurotoxic proteins. In cell models, blocking the activity of the enzymes reduced the effects of Huntington's disease.
Based on these findings, the drug discovery team obtained compounds from a variety of sources in order to prosecute a drug discovery programme. Approaches employed included fragment screening, diversity screening and virtual screening. The virtual screening used BioAscent's on-demand Compound Cloud service which provided quick access to a library of over 125,000 lead-like and drug-like IP-free compounds.
The institute undertook a Virtual Screening approach to select potential hits from Compound Cloud, downloading the structures of the 31,000 kinase inhibitor subset of the library, and selecting potential hits via a number of computational methods (filtering based on sub-structures, docking approaches using a literature crystal structure and pharmacophore approaches based on known ligands of similar targets). Based on their structures, the resulting compounds were assigned to 960 clusters.
In January 2017 the team ordered 960 compounds (10 x 96 well plates) from Compound Cloud, representing the individual clusters, and used these as part of their target-based screening. Potential hits were re-ordered for confirmatory studies.
The institute has now identified small molecule inhibitors of the PI5P4 kinases and have shown in a range of cell types, including primary neurons, that these compounds upregulate autophagy. The most advanced hits in this program are based on the initial Compound Cloud hits. These hits have been further optimised into potent and selective PI5P4 kinase inhibitors with properties consistent with those of a drug, including oral bioavailability and brain penetration in rodents. In vivo studies are ongoing to test the effects of these autophagy modulators in animal models of neurodegeneration.
Compound Cloud users can download structures of all 125,000 compounds (or pre-filtered subsets thereof), analyse structures and select only those compounds of interest, and have them delivered as liquid samples in the quantity, format and plate layout of their choosing (including near-assay ready plates). It represents an extremely cost-effective way of accessing either ready-made or customised libraries in the quantities required for a screening programme. BioAscent's integrated drug discovery team also use the library in the drug discovery programs that it carries out for its customers. 

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