Chemoinformatic prioritization of bioactive compounds associated with the bread matrix based on ChEMBL pharmacological annotations and machine learning

Abstract

Bread and cereal-based products represent not only a source of macronutrients but also a complex food matrix containing low-molecular-weight phenolic, aromatic and fermentation-derived compounds. A number of these molecules have been associated with antioxidant, anti-inflammatory, antifungal and receptor-mediated effects in experimental studies and pharmacological databases. However, these records mainly describe test systems for individual compounds and do not demonstrate the corresponding effects directly in bread products. The objective was to develop a reproducible chemoinformatics framework for internal prioritization of compounds associated with bread and cereal matrices based on structural features and ChEMBL pharmacological annotations. The study included 43 curated compounds. After structural standardization and InChIKey deduplication, 2,058 molecular features were calculated, including physicochemical descriptors and topological fingerprints. Functional labels were generated from ChEMBL records for four activity classes: antioxidant, anti-inflammatory, antifungal, and AhR-modulating. Logistic regression, random forest, CatBoost, and XGBoost were compared using nested repeated multilabel cross-validation; no independent external dataset was used in this study. Random forest showed the best balance of performance and robustness, with a macro average precision of 0.8041 (95 % CI: 0.7766–0.8320) and a macro ROC-AUC of 0.8056. The anti-inflammatory class showed the most stable performance, whereas the antioxidant class was more heterogeneous. The highest-ranking compounds were protocatechuic, caffeic, gallic and ferulic acids, quercetin, and (+)-catechin. Evaluation with molecular scaffold-based splitting reduced macro average precision to 0.6245, indicating limited transferability to structurally distant compounds. The proposed approach should be regarded as a tool for preliminary candidate selection for further external and biological validation, rather than as experimental confirmation of their functional effects in the bread matrix.