Molecular Docking, Quantum Mechanics and Molecular Dynamics Simulation of Anti-CAD Drugs Against High-Risk Xanthine Dehydrogenase Variants Associated with Oxidative Stress Pathways

Author: Ahmed, Shiek S. S. J. ; Ahmad, Sheikh F. ; Emran, Talha Bin ; Janakiraman, V. ; Attia, Sabry M. ; Sudhan, M.

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.

01 Sep 2024·Journal of Food Composition and Analysis

Ultra-high performance liquid chromatography tandem mass spectrometry for the determination of 21 β-blockers in animal-derived foods

Author: Ai, Lianfeng ; Wei, Xinxin ; Liu, Jing ; Zhang, Haichao ; Wang, Jing

A method for the simultaneous determination of 21 β-blockers in pork, beef, mutton, conditioned meat, pork liver, sheep kidney, milk, and eggs using ultra-performance liquid chromatog.-tandem mass spectrometry (UPLC-MS/MS) was developed.The samples were subjected to acidic precipitation and purified using solid phase extraction (SPE) columns.The column, mobile phase and sample preparation of the method were optimized, and the relevant methodol. was validated.The results demonstrated that the established method exhibited good linearity within the testing concentration range, with R2 values exceeding 0.99.The precisions (RSD) ranged between 0.8% and 12.43%.The limits of detection (LODs) and limits of quantitation (LOQs) for the 21 β-blockers ranged from 0.1 to 0.4μg/kg and 0.5-0.8μg/kg, resp.The average recoveries at three fortification levels ranged from 70.4% to 106.4%, with the exception of practolol, atenolol, and oxprenolol.The matrix effects ranged from 72.1% to 100.9%.The proposed method is simple, rapid, accurate, and reliable, and is suitable for the simultaneous determination of β-blockers in various animal-derived foods.

01 Jun 2024·Biomedical Chromatography

Serum metabolomics analysis combined with network pharmacology reveals possible mechanisms of postoperative cognitive dysfunction in the treatment of Mongolian medicine Eerdun Wurile basic formula

Article

Author: Tian, Mengke ; Li, Yan ; Li, Huiru ; Che, Limuge ; Qiao, Yun ; Du, Yiri ; Wang, Jiaxin ; Wang, Zhe

AbstractThis study analyzed the endogenous metabolites and metabolic pathways in the serum of Sprague–Dawley (SD) rats gavaged with the Eerdun Wurile basic formula (EWB) using metabolomics methods and network pharmacology to explore the possible mechanism of action of the EWB in improving postoperative cognitive dysfunction (POCD). SD rats were divided into the basic formula group, which received the EWB, and the control group, which received equal amounts of distilled water. The blood was collected from the abdominal aorta and analyzed for metabolite profiles using ultra‐high‐performance liquid chromatography–mass spectrometry (UHPLC–MS). Network pharmacology predicts the targets of the differential metabolites and disease targets; takes the intersection and constructs a “metabolite‐disease‐target” network; and performs protein–protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. A total of 56 metabolites were selected for significant differences between the groups, mainly affecting amphetamine addiction, alcoholism, and regulation of lipolysis in adipocytes. A total of 177 potential targets for differential metabolite action in POCD were selected. The PI3K‐Akt pathway, the HIF‐1 pathway, and the FoxO pathway were in key positions. The studies have shown that EWB could improve POCD through multicomponents, multitargets, and multipathways, providing new possibilities and reference values for the treatment of POCD.

100 Deals associated with Metipranolol Hydrochloride

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KEGG	Wiki	ATC	Drug Bank
D02081	Metipranolol Hydrochloride	S01ED04	DB01214

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