Using the BioAssay Ontology for Analyzing High-Throughput Screening Data

Abstract

High-throughput screening (HTS) is the main starting point for hit identification in drug discovery programs. This has led to a rapid increase of available screening data both within pharmaceutical companies and the public domain. We have used the BioAssay Ontology (BAO) 2.0 for assay annotation within AstraZeneca to enable comparison with external HTS methods. The annotated assays have been analyzed to identify technology gaps, evaluate new methods, verify active hits, and compare compound activity between in-house and PubChem assays. As an example, the binding of a fluorescent ligand to formyl peptide receptor 1 (FPR1, involved in inflammation, for example) in an in-house HTS was measured by fluorescence intensity. In total, 155 active compounds were also tested in an external ligand binding flow cytometry assay, a method not used for in-house HTS detection. Twelve percent of the 155 compounds were found active in both assays. By the annotation of assay protocols using BAO terms, internal and external assays can easily be identified and method comparison facilitated. They can be used to evaluate the effectiveness of different assay methods, design appropriate confirmatory and counterassays, and analyze the activity of compounds for identification of technology artifacts.

Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity

“…To avoid “rediscovering” known drugs, we gave lower priority to compounds that had a described mechanistic activity or whose chemical structure was similar to established anthelmintics [ 62 , 63 ]. We reasoned that emphasizing novel chemical backbone structures might lead to identifying biochemical pathways in the nematode that have not yet been exploited [ 64 ]. Even so some known chemical backbones did come through our filters (see below).…”

Non-stoichiometric inhibition in integrated lead finding – a literature review

“…For example, screening with assay protocols involving nucleosomes or other nucleic-acid components might benefit from a counterscreen to remove DNA intercalators [73] that would make little sense for other enzymatic targets such as proteases or kinases. In case of doubt, pilot studies, [91] if possible in dose-response mode, [92] or a retrospective analysis of appropriately annotated historical data [93] can provide first impressions of assay sensitivity and liabilities and help to explore meaningful counterscreens. Crude natural product extracts, which contain multiple molecular species per sample, pose a special challenge, as valuable stoichiometric inhibitors can be masked by non-stoichiometric inhibitors in the mixture if the latter show up in the counterscreen and thus trigger premature elimination of the sample.…”

Minimum Information and Quality Standards for Conducting, Reporting, and Organizing In Vitro Research

“…Data organization with the BAO enables new analyses and insights. Scientists at AstraZeneca used the BAO to annotate their collection of high-throughput screening data and compared their set of assays with those available in PubChem (Zander Balderud et al 2015). They extracted metrics on the utilization of assay design and detection approaches and considered over-vs. underutilization of potential technologies.…”