Excited-State Photophysics Improves Scaffold-Robust Phototoxicity Prediction and Reveals Compound-Specific State Effects
Year: 2026
Type: preprint
Abstract: Phototoxicity is controlled by light absorption and access to reactive excited states, but predictive models usually encode only a single ground-state structure. Here, a physically staged representation was evaluated on 450 compounds (192 positive, 258 negative) with 10 repeated five-fold scaffold-grouped cross-validations. Structure alone gave ROC-AUC 0.745 ± 0.018 and PR-AUC 0.668 ± 0.027. Adding parent-state xTB/sTDA photophysics increased these metrics to 0.792 ± 0.012 and 0.716 ± 0.020; microstate aggregation reached 0.807 ± 0.012 and 0.726 ± 0.017, while conformer expansion plateaued at 0.808 ± 0.010 and 0.729 ± 0.017. In 10,000 paired compound bootstraps, the largest robust ranking increment was the structure-to-parent-photophysics step (ΔROC-AUC +0.0457, 95% CI +0.0274 to +0.0643). Microstates produced a smaller rank-based increment but reduced Brier error by 0.0080 (95% CI 0.0024–0.0134). Higher-level Q-Chem calculations preserved S1/T1 ordering (r = 0.946/0.931). Matched-state calculations showed large photophysical changes for avobenzone and 2-ethylanthraquinone but weak changes for pradofloxacin and ketoprofen. The results identify excited-state information as the dominant reproducible addition beyond structure and show that molecular-state effects are chemically meaningful but heterogeneous rather than universally accuracy-enhancing.
Source: ChemRxiv
Author: Aris Tsai
Institution: Stanford University
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7214706204