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[Display omitted] • Application of QSAR with Machine Learning techniques on the Ebselen compounds as training data related to their SAR-CoV-2 protein target. • Identify the Ebselen binding conformation using the ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD). • Providing new designed compounds which meet both ligand-based drug design and structure-based drug design approaches. The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T -shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an r2 training exceeding 0.98 and an RMSE test of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC 50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design; with the potential to guide experimental synthesis and enzyme assay testing. [ABSTRACT FROM AUTHOR]

Impact mechanics of micron-scale, Al-6061 particles on sapphire and Al-6061 substrates were investigated experimentally and through simulations. Particle impact experiments were carried out by using the laser induced projectile impact test (LIPIT) and the coefficient of restitution was evaluated for impact velocities in the range of 50–950 m/s. Bonding was observed only in Al-on-Al impacts with impact velocities over 810 m/s. A continuum model of the impacts was implemented by using commercially available finite element software. The bilinear Johnson–Cook model was implemented to model the material flow effects in the ultra-high strain rate (UHSR) regime. A cohesive zone model was used for the bonding along the particle–substrate contact interface. Heat generation due to plasticity and friction, and material damage were also included in the simulations. A quantitative measure of adiabatic shear instability (ASI) was implemented into the modeling framework to search for material points that experience drop of strength during loading. A small volume of the material internal to the particle was found to experience ASI in Al-on-sapphire impacts, but this was not observed in Al-on-Al impacts. However, if the flow rule is switched to one that neglects the effects of the UHSR-regime, ASI can be predicted in regions of the particle where the finite element mesh deforms excessively. It is recommended that any study searching for ASI in high-velocity impact simulations should assess the mesh distortion carefully and use a flow rule that includes UHSR effects. • Adiabatic shear instability (ASI) is often cited as the cause of bonding in high velocity impact of metal particles. • A mathematical criterion for the ASI is introduced and simulated material response is assessed accordingly. • In impacts of micron scale Al-6061 particles ASI is predicted for rigid substrates, but it is not observed for Al-6061 substrates. • Predictions of ASI can depend on inadequate choice of material models or simulation approaches. [ABSTRACT FROM AUTHOR]

Phencyclidine (PCP) is a frequently abused dissociative agent. It causes confusion, increased tendencies toward violence, and concentration-dependent cytotoxicity after entry into the body. The parent nucleus of phencyclidine-type substances is arylcyclohexylamine, which is easy to modify; therefore, abusers and dealers can readily synthesize substitutes beyond the drug control catalog. An urgent need exists to establish screening methods for phencyclidine-type substances to provide technical support for abuse monitoring. In this study, 20 mg of hair was pulverized in 500 mL of methanol containing 0.5 ng/mL PCP-d 5. After ultrasonication, centrifugation, and filtration, the supernatant was analyzed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) operating in the multiple reaction monitoring mode. Phencyclidine-type substances were separated in 13 min on a biphenyl column using a mobile phase gradient composed of A (water, formic acid 0.1%, acetonitrile 5%, 20 mmol/L ammonium acetate) and B (acetonitrile). The developed and validated method showed good selectivity, sensitivity (limit of detection: 0.25–2 pg/mg and lower limit of quantitation: 0.5–4 pg/mg), linearity (R2 > 0.994), accuracy, and precision (< 20%), and a dilution effect. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of phencyclidine-type substances in hair from 87 authentic forensic cases. Nine analytes were detected: ketamine (10.3–26211.3 pg/mg), 2-F-2-oxo-PCE (11.5–4034.9 pg/mg), 2-FDCK (14.0–43290.2 pg/mg), 2-BrDCK (10.6–21170.0 pg/mg), nor2-FDCK (10.1–16767.4 pg/mg), tiletamine (10.1–3250.8 pg/mg), O-PCE (43.3–166.1 pg/mg), DCK (10.2–90.4 pg/mg), and norDCK (24.9–103.0 pg/mg). • A systematic screening method for 36 phencyclidine-type substances was established. • Excellent sensitivity compatible with hair analysis, LOD: 0.25–2 pg/mg. • Seven groups of isomers were effectively separated. • Applied to forensic toxicology analysis and detected 87 positive samples. [ABSTRACT FROM AUTHOR]

Nitrous oxide (N 2 O), also known as laughing gas, has a euphoric effect and is becoming increasingly popular as a recreational inhalant drug. Deaths caused by recreational nitrous oxide abuse are rare, but may still occur. Although some methods for the quantification of N 2 O by GC-MS have been reported, elimination of carbon dioxide interference and the choice of a suitable internal standard remain current limitations to accurate N 2 O quantification. Here, a validated method using headspace-gas chromatography–mass spectrometry (HS-GC–MS) is described that allows the quantification of N 2 O in human blood samples: sodium hydroxide is used to remove carbon dioxide, and n-pentane is chosen as a suitable internal standard. Collectively, the validation results show a good linear relationship of N 2 O in blood within the concentration range of 0.02 ∼ 0.5 mL/mL and an LOD of 0.005 mL/mL. Subsequent application of the validated method to two real mortality cases due to N 2 O intoxication provided reference values for blood concentrations in forensic cases. Other biological specimens (gaseous samples and tissues) of the deceased were also analyzed to demonstrate that the deaths were caused by asphyxia due to the inhalation of N 2 O. [Display omitted] • A method for the determination of N 2 O in biological matrices. • Removing possible interference from CO 2 in the detection of N 2 O. • Detection of N 2 O in blood of two decedents from acute N 2 O poisoning. [ABSTRACT FROM AUTHOR]