{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T10:17:10Z","timestamp":1780481830756,"version":"3.54.1"},"posted":{"date-parts":[[2025,3,25]]},"group-title":"Pharmacology and Toxicology","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Chemical pollution is a global threat to human health, yet the toxicity mechanism of most contaminants remains unknown. Here, we applied an ultrahigh-throughput affinity-selection mass spectrometry (AS-MS) platform to systematically identify protein targets of prioritized chemical contaminants. After benchmarking the platform, we screened 50 human proteins against 481 prioritized chemicals, including 446 ToxCast chemicals and 35 per-and polyfluoroalkyl substances (PFAS). Among 24,050 interactions assessed, we discovered 35 novel interactions involving 14 proteins, with fatty acid-binding proteins (FABPs) emerging as the most ligandable protein family. Given this, we selected FABPs for further validation, which revealed a distinct PFAS binding pattern: legacy PFAS selectively bound to FABP1, whereas replacement compounds, PFECAs, unexpectedly interacted with all FABPs. X-ray crystallography further revealed that the ether group enhances molecular flexibility of alternative PFAS, to accommodate the binding pockets of FABPs. Our findings demonstrate that AS-MS is a robust platform for the discovery of novel protein targets beyond the scope of the ToxCast program and highlight the broader protein-binding spectrum of alternative PFAS as potential regrettable substitutes.<\/jats:p>","DOI":"10.1101\/2025.03.20.644436","type":"posted-content","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T02:55:54Z","timestamp":1742957754000},"source":"Crossref","is-referenced-by-count":1,"title":["High-throughput protein target mapping enables accelerated bioactivity discovery for ToxCast and PFAS compounds"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6951-9298","authenticated-orcid":false,"given":"Diwen","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Toronto, Toronto, ON, Canada"},{"name":"Department of Physical and Environmental Sciences, University of Toronto, Toronto, ON, 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