| Autor: |
Ambe K; Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Nakamori M; Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Tohno R; Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Suzuki K; Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Sasaki T; Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 4228526, Japan., Tohkin M; Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Yoshinari K; Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 4228526, Japan. |
| Jazyk: |
angličtina |
| Zdroj: |
Chemical research in toxicology [Chem Res Toxicol] 2024 Nov 18; Vol. 37 (11), pp. 1843-1850. Date of Electronic Publication: 2024 Oct 20. |
| DOI: |
10.1021/acs.chemrestox.4c00168 |
| Abstrakt: |
The prediction of cytochrome P450 inhibition by a computational (quantitative) structure-activity relationship approach using chemical structure information and machine learning would be useful for toxicity research as a simple and rapid in silico tool. However, there are few in silico models focusing on the species differences between rat and human in the P450s inhibition. This study aimed to establish in silico models to classify chemical substances as inhibitors or non-inhibitors of various rat and human P450s, using only molecular descriptors. Using the in-house test results from our in vitro experiments, we used 326 substances for model construction and internal validation data. Apart from the 326 substances, 60 substances were used as external validation data set. We focused on seven rat P450s (CYP1A1, CYP1A2, CYP2B1, CYP2C6, CYP2D1, CYP2E1, and CYP3A2) and 11 human P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Most of the models established using XGBoost showed an area under the receiver operating characteristic curve (ROC-AUC) of 0.8 or more in the internal validation. When we set an applicability domain for the models and confirmed their generalization performance through external validation, most of the models showed an ROC-AUC of 0.7 or more. Interestingly, for CYP1A1 and CYP1A2, we discovered that a human P450 inhibitory activity model can predict rat P450 inhibitory activity and vice versa. These models are the first attempts to predict inhibitory activity against a wide variety of P450s in both rats and humans using chemical structure information. Our experimental results and in silico models would be helpful to support information for species similarities and differences in chemical-induced toxicity. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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