Qualitative and quantitative in silico toxicity profiling of "angel dust": phencyclidine (PCP) analogues as new psychoactive substances (3-HO-PCP, 3-MeO-PCP, 4-MeO-PCP, 3-HO-PCE, 3-MeO-PCE, 4-MeO-PCE).

Abstract

Phencyclidine (PCP), historically known as "angel dust," and its analogues (3-HO-PCP, 3-MeO-PCP, 4-MeO-PCP, 3-HO-PCE, 3-MeO-PCE, 4-MeO-PCE) are dissociative new psychoactive substances with high abuse potential and limited experimental safety data. An integrated in silico workflow (STopTox, admetSAR 3.0, ADMETlab 3.0, ACD/Labs Percepta, Toxtree, ProTox 3.0, OCHEM, TEST, VEGA QSAR) was applied to profile acute toxicity and key hazard domains. Across platforms, rat oral LD50 values for PCP-type analogues were consistently in the ~ 200-630 mg/kg range (Percepta 210-800 mg/kg, TEST 197-628 mg/kg, VEGA 278-368 mg/kg, ProTox ~ 348-404 mg/kg), indicating moderate acute toxicity by the oral route; substantially lower LD50 values were predicted for intravenous exposure in mice (~ 25-59 mg/kg). Qualitative models (STopTox, ADMETlab, admetSAR) classified all compounds as acutely toxic by the oral route (e.g., STopTox oral toxicity confidence ~ 77-92%) and commonly predicted inhalation/dermal risks depending on the analogue; admetSAR assigned EPA Category III for acute oral toxicity. Organ-specific effects (Percepta; ADMETlab) highlighted the lungs, liver, and blood as prominent targets (e.g., lungs 0.89-0.93, liver up to 0.91, blood up to 0.85), with gastrointestinal involvement (up to 0.82) and generally lower kidney probabilities (~ 0.09-0.70). Cardiotoxicity signals included predicted hERG inhibition with Percepta IC50 ~ 4.9-12.3 µM and high probabilities of hERG blockade in ADMETlab/admetSAR, supporting potential QT-prolongation risk. Genotoxicity predictions were consistently negative across Percepta, OCHEM, ADMETlab, admetSAR, and VEGA. Eye/skin irritation potential was notable for phenolic analogues, with Percepta indicating high probabilities for 3-HO-PCP and 3-HO-PCE (eye ~ 88-90%, skin ~ 96%), while other tools showed model-dependent variability. Endocrine screening suggested at most weak-to-moderate ER-α interactions, with the highest probability for 3-HO-PCP (LogRBA > - 3). Overall, convergent multi-tool evidence indicates moderate acute toxicity, cardiotoxicity signals, and multi-organ risk for PCP analogues, while mutagenicity appears unlikely. These results provide mechanistic and quantitative context to inform clinical management, forensic interpretation, and risk assessment of this NPS class.