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In silico and cheminformatics enrichment analysis to increase confidence in in vitro high-throughput screening (HTS) results: Application to Tox21 thyrotropin-releasing hormone receptor (TRHR) assay
Citation:
Shobair, Mahmoud A., D. Chang, R. Lougee, K. Paul-Friedman, Chris Grulke, J. Zhao, R. Huang, M. Xia, AND A. Richard. In silico and cheminformatics enrichment analysis to increase confidence in in vitro high-throughput screening (HTS) results: Application to Tox21 thyrotropin-releasing hormone receptor (TRHR) assay. QSAR 2021 International Workshop on QSAR in Environmental and Health Sciences, Virtual, NC, June 07 - 10, 2021. https://doi.org/10.23645/epacomptox.15101949
Impact/Purpose:
Presentation to the QSAR 2021 International Workshop on QSAR in Environmental and Health Sciences June 2021. Chemotyping, the annotation of observed activities at a fragment, substructure, or scaffold level, provides a way to abstract chemical detail from the broader activity signature that is correlated with a particular fragment. This approach is an effective profiling mechanism and allows navigation of complex data landscapes, such as ToxCast, to understand relationships between an activity and fragment to develop a weight¿of¿evidence regarding a particular chemical and its potential liabilities. Applying and refining the approach towards an array of datasets and research applications will inform the development of standardized workflows and tools. The results of these efforts will be of direct benefit to program and regional offices as well as the greater scientific community in expanding the utility of NAMs through structure¿based concepts.
Description:
Despite progress in applying high-throughput screening (HTS) technologies to toxicology, exemplified by the Tox21 and ToxCast programs, the challenge of relating biochemical outputs to molecular initiating events (MIEs) and adverse outcome pathways (AOPs) remains challenging. To increase confidence in HTS results for hazard evaluation, a structure-based data enrichment and knowledge contextualization workflow was developed to identify likely false positives and discriminate true receptor binders. The tiered approach was used to evaluate in vitro Tox21 assay quantitative HTS data for the thyrotropin-releasing hormone receptor (TRHR), an MIE in the thyroid hormone AOP. The tiered approach: 1) identifies structure-activity patterns using chemotype-enrichment analysis; 2) filters actives due to cytotoxicity and assay interference; and 3) uses 3D pharmacophore modeling to prioritize chemicals capable of binding to TRHR. Results from TRHR competitive binding literature studies were curated as a training set for pharmacophore modeling, the latter indicating that less than 11% of Tox21_TRHR actives contain TRH-like binding features. Results from these structure-based analyses were combined into a tiered, decision-tree workflow and applied to the Tox21_TRHR dataset, first to prioritize potential true positives within the agonist and antagonist “actives”, and second to identify a small set of potential false negatives with compelling structure-based evidence for true activity. The presented workflow is grounded by structural determinants directly related to relevant signals in experimental results and can be generalized to other HTS datasets to increase the value of in vitro data for chemical prioritization. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: In silico and cheminformatics enrichment analysis to increase confidence in in vitro high-throughput screening (HTS) results: Application to Tox21 thyrotropin-releasing hormone receptor (TRHR) assay
QSAR2021_POSTER#252_TRHR_MSHOBAIR_FINAL.PDF (PDF, NA pp, 2763.467 KB, about PDF)