Microstate-Aware Excited-State Descriptors Improve Scaffold-Robust Prediction of Drug Phototoxicity
Year: 2026
Type: preprint
Abstract: Drug phototoxicity depends on electronically excited states whose energies and intensities can change with protonation, tautomerism, and conformation, yet most predictive models represent a single parent structure. We evaluated a molecular-state-aware workflow on a curated 450-compound in vitro photoirritation (PIV) benchmark expanded to 1,088 microstates. Across 10 repeated 5-fold scaffold-held-out cross-validations, mean ROC-AUC increased from 0.745 for structure alone to 0.792 after adding parent xTB+sTDA descriptors, 0.807 with microstate summaries, and 0.808 with conformer aggregation; PR-AUC increased from 0.669 to 0.727. Compound-paired bootstrap analysis gave a full-model ROC-AUC gain of +0.0569 (95% CI 0.0234-0.0908) and PR-AUC gain of +0.0533 (0.0133-0.0933). Higher-level Q-Chem calculations preserved screening excited-state ordering (S1 Pearson r = 0.946; T1 r = 0.931), and an additional preselected state panel completed 22/24 TDA jobs with all four parent-alternate microstate pairs available. These pairs showed substantial state-dependent changes, including a 240.4 to 259.0 nm bright-state shift for trinexapac-ethyl. Clinical PIH endpoint transfer was modest (n = 155; ROC-AUC 0.609), consistent with endpoint and chemical-space shift. The results support molecular-state-aware excited-state featurization as a mechanistically grounded strategy for computational photosafety.
Source: ChemRxiv
Author: Aris Tsai
Institution: Stanford University
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214775764