Toxicity of fentanyl (CAS: 437-38-7) and valerylfentanyl (CAS: 122882-90-0): the first integrative in silico toxicology study with clinical and forensic implications.

Fentanyl and its analog valerylfentanyl (CAS: 122882-90-0) represent a major toxicological threat amid the ongoing opioid crisis. Using an integrative in silico approach (STopTox, ProTox 3.0, TEST 5.1.2, VEGA QSAR, Percepta, ADMETlab, admetSAR), we evaluated key toxicity end points relevant to clinical and forensic toxicology. Valerylfentanyl exhibited high acute toxicity with predicted LD50 values as low as 18.0 mg/kg (ProTox) and 150.13 mg/kg (TEST). Both compounds showed strong potential to inhibit the hERG potassium channel (95.7% for valerylfentanyl), indicating a substantial risk of cardiotoxicity. Predicted organ-specific effects were most prominent in the lungs (94%), cardiovascular (89%), and gastrointestinal systems (81%), with moderate impact on kidneys and blood. Skin irritation potential was high (up to 81.6%), while genotoxicity remained low, though valerylfentanyl showed non-negligible mutagenic probability in some models. The structural analysis identified piperidine-related toxicophores responsible for these effects. Our findings confirm that minor structural modifications can significantly alter toxicological profiles. These results underscore the application of integrated in silico approach for rapid, ethical hazard identification of emerging NPS, supporting their critical application in both clinical and forensic toxicology.