Combined In Vitro and In Silico Workflow to Deliver Robust, Transparent, and Contextually Rigorous Models of Bioactivity

• DOI: 10.1021/acs.jcim.5c00713
• Publication Date: 2025-04-24T19:35:51Z
• Authors: Nathaniel Charest; Gabriel Sinclair; Stephanie A. Eytc...; Daniel T. Chang; Todd M. Martin; Charles N. Lowe; Katie Paul Friedman; Antony J. Williams

New approach methodologies (NAMs) are an increasing priority in the field of toxicology to fill data gaps and reduce time resources chemical safety assessment. We describe NAMs workflow that integrates vitro high-throughput bioassay with silico computational model. In defining this workflow, we propose, as a crucial step development, identification explicit "purpose contexts": priori definitions scope intent solution, which provide natural targets for mechanistic interpretation, validation, output design By inspecting from assay measuring displacement fluorescent probe 8-anilino-1-naphthalenesulfonic acid (ANSA) serum transport protein transthyretin (TTR) proxy potential disruption thyroxine (T4) binding, collaboration experimenters, developed three relevant purpose contexts modeling effort: (1) examination confirmation principle via orthogonal information, (2) immediate integration experimental cycle costs enhance hit rates, (3) ultimate replacement use single-concentration screening prioritization strategy bioactivity testing bulk libraries. From these contexts, derived foundations robust transparent quantitative structure-activity relationship (QSAR) model is constructively fit purpose, characterized by first-principles analysis, strict quality evaluation, contextually rigorous performance and, finally, delivery recommendation schedule simultaneously improve rates learning potential.