Greater Binding Research Articles

Screening of Some Ayurvedic Phytochemicals to Identify Potential Inhibitors against SARS-CoV-2 Mpro by In Silico Computational Approach

Background: The classical drug discovery approach demands more than a decade of strenuous exploration and substantial monetary or economic support, which is difficult in pandemic conditions, such as COVID-19. Methods: The main purpose of this work was to ascertain the best inhibitors to combat the SARS-CoV-2 Mpro (PDB ID: 6LU7) target. To achieve this, we conducted a molecular docking screening of 35 phytochemicals from eight different medicinal plants. Using a structure-based drug design of molecular docking, we studied the binding affinities and found 35 molecules that showed greater or identical affinity towards the target than the N3 inhibitor. Additionally, we conducted MD simula-tions for the 6LU7-schaftoside complex. Results: The docking analysis has identified several promising phytochemicals with great binding attraction towards the key target. The phytoconstituent, schaftoside (-8.7 kcal/mol), demonstrated the most binding attraction with the target via 6 conventional hydrogen bonds. Additionally, 2'-O-methyl cajanone (-8.3 kcal/mol), isoschaftoside (-8.0 kcal/mol), cajaflavonone (-8.0 kcal/mol), and co-crystal N3 inhibitor (-7.8 kcal/mol) also displayed significant binding affinity. Interestingly, schaftoside and 2’-O-methyl cajanone showed the most promising activities with their low binding energies. Conclusion: After thorough analysis, some compounds were found on elite docking sites that re-sembled drugs and had a harmless ADMET profile. Based on the study, it can be concluded that the compounds mentioned earlier possess the ability to be reused as potent inhibitors against the COVID-19 pandemic.

Development of a magnetic separation method for rapid isolation and enrichment of bacteria in raw pork using chitosan functionalized magnetic Fe3O4@MIL-100(Fe) composites.

In this study, a pretreatment method based on a magnetic capture probe for the rapid isolation and enrichment of bacteria from raw pork was developed. The chitosan immobilized Fe3O4@MIL-100(Fe) was prepared as a capture probe for total bacterial counts through the electrostatic interaction of positively charged chitosan and the negatively charged substances on the surface of bacteria. The interference of matrix in pork samples on this method was studied and removed by differential centrifugation. The results showed the capture probe had a great selectivity binding and magnetic separation properties for the tested six common bacteria in pork. Under the optimal conditions, the capture efficiency of the bacteria (105 CFU mL-1) from pork surface samples was all above 90%. The capture efficiency of the bacteria in a homogenate system was greatly decreased due to the interference of sarcoplasmic protein and myofibrillar protein in pork. The matrix effect was mitigated by a differential centrifugation method, and the capture efficiency of all six bacteria was >80%. The developed magnetic separation method took 40min and showed good isolation and enrichment properties of bacteria. Thus, the proposed method is expected to provide a simple, convenient, and time-saving pretreatment method for the detection of total bacterial counts in pork.

Design, synthesis, and antitumor activity evaluation of 1,2,3-triazole derivatives as potent PD-1/PD-L1 inhibitors

A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both in vitro and in vivo. Among them, compound III-4 demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC50 value of 2.9 nM and a KD value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3+ T cells assay, III-4 relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 μg/mL). Moreover, compound III-5, an ester prodrug derived from III-4, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound III-5 holds promise as an inhibitor of the PD-1/PD-L1 interaction for cancer immunotherapy.

Qianyang yuyin granule ameliorates mitochondrial dysfunction of hypertensive myocardial remodeling

Ethnopharmacological relevanceClinical studies have found that Qianyang Yuyin granule (QYYYG), a kind of oral Chinese patent medicine, had definite clinical effect for hypertensive myocardial remodeling. However, the potential mechanism is not entirely clear. Aim of the studyThe purpose of this research was to explore the underlying mechanism QYYYG on the treatment of hypertensive myocardial remodeling. Materials and methodsAnalysis the transcriptome data from the NCBI public platform GEO database and our study to explore the key pathological change of myocardial tissues in hypertensive mice and the main pathway of QYYYG in treating hypertensive myocardial remodeling. Network pharmacological analysis was used to predict the potential target of QYYYG. The molecular docking and molecular dynamics simulation was used for molecular binding analysis of specific compounds and target proteins. In the experiment in vivo, the effect of QYYYG on hypertensive myocardial remodeling and myocardial mitochondrial dysfunction in hypertensive mice caused by Ang Ⅱ was estimated. In the experiment in vitro, the Ang Ⅱ-induced myocardial remodeling model in H9c2 cells was constructed, and the effect of QYYYG on ameliorating myocardial remodeling and mitochondrial dysfunction was evaluated. ResultsTranscriptome analysis suggested that mitochondrial dysfunction was a key pathological change of myocardial tissues in hypertensive mice, and QYYYG could improve hypertensive myocardial remodeling through enhancing mitochondrial biogenesis to repair myocardial mitochondrial dysfunction. Network pharmacological analysis predicted that SIRT1 was an important potential target of QYYYG in treating hypertensive myocardial remodeling, and basically all the active components, especially quercetin, had a great binding affinity with SIRT1. Experiments in vivo proved that QYYYG had great efficacy hypertensive myocardial remodeling in Ang Ⅱ-treated mice. It was found that QYYYG improved the quality and quantity of mitochondria, and increased SIRT1 levels in myocardial tissue of Ang Ⅱ-treated mice. In Ang Ⅱ-treated H9c2 cells, with intervention of QYYYG, myocardial remodeling and myocardial mitochondrial dysfunction was ameliorated. In addition, QYYYG up-regulated SIRT1 expression and enhanced mitochondrial biogenesis in Ang Ⅱ-treated H9c2 cells. ConclusionThis study suggested that mitochondrial dysfunction was an important pathological change of myocardial tissues in hypertensive mice. QYYYG might ameliorate the mitochondrial dysfunction of hypertensive myocardial remodeling through up-regulating SIRT1 expression to enhance the mitochondrial biogenesis.

Mitigating PTFE decomposition in ultra thick dry-processed anodes for high energy density lithium-ion batteries

Dry electrode technology is a next-generation method for manufacturing lithium-ion batteries because it is useful for fabricating thick electrodes without solvents, facilitating high energy densities and cutting down on the battery manufacturing costs. However, the commonly used polytetrafluoroethylene (PTFE) binder in dry electrode technology undergoes severe decomposition in dry-processed anodes during the first lithiation process due to its low lowest unoccupied molecular orbital level. This phenomenon seriously aggravates battery performance, such as in terms of the initial coulombic efficiency and cycle life. Thus, a strategy to suppress this irreversible reaction of PTFE should be established for dry-processed anodes to increase the energy density of LIBs without adverse effects on battery performance. To address this challenge, in this work, fluoroethylene carbonate (FEC) as an electrolyte additive has been introduced to form a preemptive and stable FEC-derived solid electrolyte interface (SEI) to protect a graphite and the PTFE binder. This SEI considerably alleviates the irreversible reaction of PTFE, thereby securing the reversible capacity and maintaining the structure of the electrode through the great binding properties. These results provide guidance for increasing the electrochemical stability in dry-processed anode systems, which gets closer the innovative dry anode technology for cost-effectiveness and high energy density.

Novel PLGA-encapsulated-nanopiperine promotes synergistic interaction of p53/PARP-1/Hsp90 axis to combat ALX-induced-hyperglycemia

The present study predicts the molecular targets and druglike properties of the phyto-compound piperine (PIP) by in silico studies including molecular docking simulation, druglikeness prediction and ADME analysis for prospective therapeutic benefits against diabetic complications. PIP was encapsulated in biodegradable polymer poly-lactide-co-glycolide (PLGA) to form nanopiperine (NPIP) and their physico-chemical properties were characterized by AFM and DLS. ∼ 30 nm sized NPIP showed 86.68% encapsulation efficiency and − 6 mV zeta potential, demonstrated great interactive stability and binding with CT-DNA displaying upsurge in molar ellipticity during CD spectroscopy. NPIP lowered glucose levels in peripheral circulation by > 65 mg/dL compared to disease model and improved glucose influx in alloxan-induced in vivo and in vitro diabetes models concerted with 3-folds decrease in ROS production, ROS-induced DNA damage and 27.24% decrease in nuclear condensation. The 25% increase in % cell viability and inhibition in chromosome aberration justified the initiation of p53 and PARP DNA repairing protein expression and maintenance of Hsp90. Thus, the experimental study corroborated well with in silico predictions of modulating the p53/PARP-1/Hsp90 axis, with predicted dock score value of − 8.72, − 8.57, − 8.76 kcal/mol respectively, validated docking-based preventive approaches for unravelling the intricacies of molecular signalling and nano-drug efficacy as therapeutics for diabetics.

Exploring Nephroprotective Properties of <i>Wedelia chinensis: In Vitro, In Silico,</i> and <i>In Vivo</i> Investigations

The purpose of this research work is to investigate the nephroprotective efficacy of Wedelia chinensis leaf extracts against gentamicin-induced nephrotoxicity for in vitro, in silico, and in vivo techniques. The extracts of Wedelia chinensis leaf rich in flavonoids were subjected to an in silico method for ligands and target proteins. The results of the in vitro antioxidant study of extracts were tested for cytoprotective MTT assay and anti-inflammatory efficacy by protein denaturation assay using Human Embryonic Kidney cells (HEK293). The in vivo nephroprotective potential of the extract was evaluated with the two doses of 250mg/kg and 500mg/kg body weight in gentamicin nephrotoxicity in rats. The biochemical parameters observed for changes in the histopathology of the kidney. While comparing with other extracts of Wedelia chinensis Hydroalcoholic Extract (WCHAE) shows great binding affinity with bonding interactions of flavonoids and phenolics-based ligands observed with the target proteins that provided early information. The in vitro cell lines study revealed no cytotoxicity and better anti-inflammatory effect on HEK293 cells with cytoprotective and nephroprotective efficacy of WCHAE. The in vivo nephroprotective activity improved at a dose of 500mg/kg of WCHAE than Wedelia chinensis Ethanolic Extract (WCEE). The histopathological findings revealed the improvement in gentamicin-induced renal toxicity by the WCHAE orally treated group compared to normal and negative control groups. These results of WCHAE are more satisfactorily effective than WCEE with marked in vitro antioxidant, and cytoprotective effects in HEK293 cells. In in silico docking, it shows good interaction scores of ligands for target proteins like (kidney injury molecule) KIM-1 and Neutrophil Gelatinase-Associated Lipocalin (NAGAL) that helps to correlate nephroprotective potential benefits of antioxidants in plant extracts against gentamicin induced nephrotoxicity in rats.

“Molecular Docking Analysis Of Alpha-Terpineol Against Matrix Metalloproteinases”

Objectives: The process of wound healing is crucial and complex within the human body, involving various enzymes. Increased concentrations of matrix metalloproteinases (MMPs) at the wound site lead to slowdown in the healing process. Small bioactive compounds produced from natural sources can be used to down-regulate or inhibit these over expressed MMPs. Alpha-terpineol, a mono-terpenoid alcohol with a monocyclic structure, is present in vitex negundo linn leaf, pemus boldus leaf, cajeput oil, coriander oil, and pine oil. It exhibits diverse biological uses, serving as an antioxidant, anticancer, anticonvulsant, antiulcer, anti-inflammatory, antihypertensive, and anti-nonciceptive agent. The work aims to use molecular docking to understand how alpha-terpineol binds to MMPs. Materials and Methods: The MMPs was obtained from RCSB database and the alpha-terpineol was obtained from Pubchem. The Auto Dock software was used to create a molecular docking of alpha-terpineol activity on MMPs. Alpha-Terpineol binds to MMPs receptors. Auto Dock Vina was used to examine the binding box-related files, including a PDBQT file and PYMOL software was then used to analyze the receptor and ligand PDBPT files. Result: Docking tests revealed that alpha-terpineol has a great binding affinity for all four MMPs tested. MMPs 3, 8, and 12 had free binding energies of around -9.1, -10.5, and -9.7kcal/mol, respectively. Conclusion: Therefore, alpha-terpineol can be employed to regulate the function of matrix metalloproteinases and facilitate the process of wound healing.

A silver cluster-assembled material as a matrix for enzyme immobilization towards a highly efficient biocatalyst.

Silver cluster-assembled materials (SCAMs) epitomize well-defined extended crystalline frameworks that combine the ingenious designability at the atomic/molecular level and high structural robustness. They have captivated the interest of the scientific fraternity because of their modular construction which enables to systematically tailor their functions, and their capacity to not only inherit the characteristics of component building units but also introduce their uniqueness in endowing the final material with extraordinary properties. Herein, we demonstrate the synthesis of a novel (3,6)-connected two-dimensional (2D) SCAM [Ag12(StBu)6(CF3COO)6(THIT)6]n (described as TUS 5, THIT = 2,4,6-tri(1H-imidazol-1-yl)-1,3,5-triazine) composed of Ag12 cluster nodes and tritopic imidazolyl linkers. We have leveraged, for the first time, this precisely architected extended SCAM structure as a support matrix for enzyme immobilization. The electrostatic attraction between the negatively charged amano lipase PS and positively charged TUS 5 as well as the surface hydrophobicity of TUS 5 catered to great binding of lipase onto the TUS 5 matrix, in addition to boosting the activity of lipase via interfacial activation. Capitalizing on the cooperative benefits of organic and inorganic support matrices wherein organic supports impart with cost-efficiency, biocompatibility, and improved enzyme stability and reusability and inorganic supports confer high thermal, mechanical and microbial resistance, we have utilized the immobilized lipase on TUS 5 SCAM (lipase@TUS 5) for the kinetic resolution of (R,S)-1-phenylethanol by transesterification reaction. Importantly, lipase@TUS 5 could attain appreciably higher conversion into (R)-1-phenylethyl acetate, besides featuring superior thermal stability, solvent tolerance and recyclability, over the native lipase.

EGFR-targeting peptide conjugated polymer-lipid hybrid nanoparticles for delivery of salinomycin to osteosarcoma.

Salinomycin (SAL) is a chemotherapeutic drug with anti-osteosarcoma efficacy, but its hydrophobic properties have hindered its application. Nanoparticles have been widely used as drug carriers to improve the solubility of hydrophobic drugs. The dodecapeptide GE11 has been shown to have great binding affinity to the epidermal growth factor receptor (EGFR), which is highly overexpressed in osteosarcoma. We designed novel SAL-loaded GE11-conjugated polymer-lipid hybrid nanoparticles (GE11-NPs-SAL) to target osteosarcoma. The characterization and antitumor activity of GE11-NPs-SAL were evaluated both in vitro and in vivo. The results showed that GE11-NPs-SAL had a size of ~100 nm with a high encapsulation efficacy of ~80%. Compared with the non-targeted nanoparticles, GE11-NPs-SAL showed increased internalization in osteosarcoma cells and improved therapeutic efficacy in osteosarcoma both in vitro and in vivo. GE11-NPs-SAL is a promising treatment for osteosarcoma.

The discovery of subunit-selective GluN1/GluN2B NMDAR antagonist via pharmacophere-based virtual screening.

The incidence and mortality rates of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are gradually increasing worldwide. Numerous studies have demonstrated that N-methyl-D-aspartic acid receptor (NMDAR)-mediated excitotoxicity contributes to neurodegenerative diseases. Ifenprodil, a subtype-selective NMDAR antagonist, showed strong therapeutic potential. However, it suffers from low oral bioavailability and off-target side effects. In this study, natural compounds were identified for selective inhibition of GluN1/GluN2B NMDAR of human. We obtained a set of natural compounds (n = 81,366) from COCONUT, TIPdb, PAMDB, CMNPD, YMDB, and NPAtlas databases, and then virtually screened by an ifenprodil-structure-based pharmacophore model and molecular docking. The top 100 compounds were selected for binding affinity prediction via batch drug-target affinity (BatchDTA). Then, the top 50 compounds were analyzed by absorption, distribution, metabolism, excretion, toxicity (ADMET). Molecular dynamics involving molecular mechanics/position-Boltzmann surface area (MM-PBSA) calculation were performed to further screening. The top 15 compounds with strong binding affinity and ifenprodil, a proven GluN2B-selective NMDAR antagonist, were subjected to molecular dynamic simulations (100 ns), root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), H-bonds, solvent accessible surface area (SASA), principal component analysis (PCA), and binding free energy calculations. Based on these analyses, one possible lead compound carrying positive charges (CNP0099440) was identified, with great binding affinity and less off-target activity by contrast to ifenprodil. CNP0099440 has great potential to be a GluN1/GluN2B NMDAR antagonist candidate and can be further detected via in vitro and in vivo experiments.

Investigating the molecular mechanisms of Ashwagandha phytocompounds in epilepsy through differential gene expression and pathway analysis

Introduction and Aim: Withania somnifera (Ashwagandha) is a traditional Indian herb used in Ayurveda and Unani medicine, particularly in anti-inflammatory, anti-cancer, anti-stress, antioxidant, immune-boosting, and rejuvenating effects. Epilepsy is a severe neuropsychological condition that occurs sporadically and has a long-term effect on the electrical signals that travel between brain cells. The disorder is characterized by recurrent seizures that are brought on by a sudden increase in brain electrical activity. This is the outcome of abnormal neuronal discharges or coordinated neuronal hyperexcitability. The study’s main objective is to find out the therapeutic phytocompound in treating Epileptic disorder. Materials and Methods: This study investigated the potential use of phytochemicals from the Ashwagandha plant as epileptic seizure treatments that target key genes strongly associated with the disease. To forecast the binding affinity between the phytochemicals and the receptors, molecular docking simulations (PyRx) were used for the virtual screening. Results: The preliminary screening of the twenty-two phytocompounds from Withania somnifera was based on their affinity for epilepsy. The results showed that withasomnine exhibited great binding affinity to the receptors, indicating their potential as targeted epileptic seizure therapeutics. The ligands revealed stronger binding with the epilepsy targets, and the binding score less than -7 kcal/mol was taken into consideration for further exploration. This research lays the groundwork for upcoming in-vitro and in-vivo studies to confirm the effectiveness of these phytochemicals as cancer therapies. Conclusion: The results suggest that withasomnine derivatives from Withania somnifera could be a promising source of epilepsy therapies.

Nitrogen-doped carbon particles with distinctive ethylene adsorption selectivity for efficient ethylene/acetylene separation

Separation of ethylene/acetylene (C2H4/C2H2) mixtures with C2H4-selective adsorbents is of economics and energy efficiency to purify crude C2H2 from methane pyrolysis or partial oxidation (POX) process. Herein, a systematic study was carried out to investigate the structural properties and C2H4/C2H2 separation performance of novel nitrogen-doped carbon particles, as well as the mechanism of preferentially adsorbing C2H4 over C2H2 through the Grand Canonical Monte Carlo (GCMC) simulations. The nitrogen-doped carbon particles derived from coconut shell and metronidazole present regular particle sizes centering at 710 μm and excellent crushing strength of 89 N. Well-developed microporosity with pore dimension mainly ranging in 0.54–0.68 nm, and fine-tuning surface chemistry with abundant nitrogen-containing species (pyridinic N, pyrrolic N and graphitic N) were observed in nitrogen-doped carbon particles. Interestingly, nitrogen-doped carbon particles exhibit preferential adsorption of C2H4 over C2H2, and the IAST-predicted selectivity of 1.5-N-CP reaches as high as 5.2 for C2H4/C2H2 (1/9) mixture at 1.0 bar and 25 °C. Remarkably, the separation stability and recyclability with complete separation for C2H4/C2H2 were well maintained during cyclic dynamic breakthrough experiments. GCMC simulation results demonstrate that the graphitic N with great binding energy (−22.61 kJ/mol for C2H4 and −19.87 kJ/mol for C2H2) favors the adsorption of both C2H4 and C2H2. The pore dimension ranging 0.54–0.68 nm, together with pyridinic N and pyrrolic N species significantly enhance the separation of C2H4/C2H2 through the large difference in adsorption interactions between C2H4 and C2H2. Therefore, the nitrogen-doped carbon particles have the excellent application accessibility in purifying C2H2 from C2H4/C2H2 mixture.

Molecular mechanism of Yi-Qi-Yang-Yin-Ye against obesity in rats using network pharmacology, molecular docking, and molecular dynamics simulations

The increasing prevalence of obesity globally, which as well as affecting people's daily lives and increasing the risk of obesity complications, also threatens the health of animal organisms simultaneously. It’s been reported that Yi-Qi-Yang-Yin-Ye had remarkable efficacy in the treatment of obesity. The specific underlying mechanism of action of Yi-Qi-Yang-Yin-Ye in treating obesity, however, remains ambiguous. Therefore, the innovative approach, which is network pharmacology combined with molecular docking and molecular dynamics simulations, was employed in the current research to explore the potential mechanism and promote further development in the treatment of obesity. The active ingredients and related targets of Yi-Qi-Yang-Yin-Ye and related targets of obesity were summarized from extensive public databases. Furthermore, network topology analysis and pathway enrichment analysis were performed to explore the complicated interactions between drug and targets. Finally, accurate validation methods composed of molecular docking and molecular dynamics simulations were conducted to elucidate the binding affinity of Yi-Qi-Yang-Yin-Ye with obesity-related targets. As a result, 13 main active ingredients and 5 core targets of Yi-Qi-Yang-Yin-Ye against obesity in rats were acquired through primary screening of network topology analysis. Pathway enrichment analysis demonstrated that intersectional targets were involved in multiple signaling pathways, where PI3K-Akt signaling pathway, MAPK signaling pathway, and Insulin resistance were the main pathways of Yi-Qi-Yang-Yin-Ye in treating obesity in rats. Finally, molecular docking indicated that the seven critical active ingredients displayed great binding affinity to the hub targets. Furthermore, molecular dynamics simulations further screened and obtained that five critical active ingredients acting on the Mapk1 target for Yi-Qi-Yang-Yin-Ye against obesity in rats. The innovative approach and the results achieved have further contributed to and revealed the molecular mechanisms for treating obesity, providing an alternative for treating obesity in animals and humans.

Anticaries Potential of Temu Kunci-Serai Ethyl Acetate Extract Combination: In Vitro and Molecular Studies Approach

Dental caries is one of the problems in dental disorders suffered by many people. There have been many ways of handling such as using temu kunci and lemongrass plants. This study aims to determine the antibacterial activity of caries in vitro and predict the mechanism of action of the bacteria that cause caries Streptococcus mutans. Temu kunci and lemongrass were extracted using ethyl acetate solvent. antibacterial tests against Streptococcus mutans were carried out using diffusion tests with a combination treatment of temu kunci: serai extracts 5% b/v: 5% b/v, 5% b/v: 10% b/v, and 10% b/v: 5% b/v. The positive control used amoxicillin and DMSO as a negative control. Potency as an anticaries drug of drived compound from Temu Kunci and Serai were evaluated by molecular docking using glucosyltransferase (3AIC). The results showed that the combination of temu kunci and serai with concentration 10% b/v: 5% b/v has potential as anticaries against Streptococcus mutans. Molecular studies depicted that Panduratin A, Isopanduratin, and 1,3-O-di-p-coumaroylglycerol have great activity toward 3AIC, respectively. Especially for Panduratin A and Isopanduratin, those compound depicted great and similar binding affinity (-8.4 kcal mol-1) that lower than Acarbose as native ligand (-8.3 kcal mol-1). Furthermore, those compound binding similarity ilustrated activity mechanism similarly with native ligand toward receptor. Additionally, the profiling drug-target interaction suggested Temu Kunci’s derived compounds have great potential as anticaries treatment.

Ciprofloxacin analogues: drug likeness, biological and molecular docking studies

The search for new antimicrobial agents due to the development of antimicrobial resistance is one of the greatest points of concern among medicinal chemists. It has been observed that the infections due to the antimicrobial resistance pathogens are one of the reasons for the mortality. Therefore, it is really important to find out some new low molecular weight antimicrobial drugs with different mode of action. Despite of being a better antibiotic, ciprofloxacin represented resistance against many pathogens. Herein, this study reported the synthesis of novel analogues of ciprofloxacin (1) including 1,3,4-oxadiazole, thiazolidine-4-one, 1,3,4-oxazoline, 1,2,4-triazole, Schiff's base, hydrazide, and 1,3,4-thiadiazole (2–8), following their computational assessment. All analogues were then synthesized and characterized using FT-IR, NMR, Mass spectroscopy, etc. The prepared analogs were then assessed for antimicrobial properties against bacterial pathogens and fungal isolates using disc diffusion and serial dilution methodology. To observe the toxicity of the prepared analogs the MTT assay was performed against HepG2 cells. The receptor glucosamine-6-phosphatase (GlcN-6P) and lanosterol 14-alpha-demethylase (CYP51) were used for the molecular docking assay using Auto Dock Tools-1.5.6 to evaluate the degree of hydrogen bonding and binding affinities. It was observed that analogue (2) established strong hydrogen bonds with the both receptors, with great binding affinities.

Polydopamine- and MOFs-based molecularly imprinted microfiltration membranes in syringe filter for selective capture of thiamphenicol, florfenicol and chloramphenicol in milk samples

In this study, molecularly imprinted microfiltration membranes (MIMFMs) based on polydopamine and metal–organic framework were innovatively proposed, and successfully prepared for capturing thiamphenicol, florfenicol and chloramphenicol from milk samples through syringe filter device. The provision of PDA and coupling of MOF particles enabled the filter membranes to have great permeability and binding capacity. Cleverly, hydrophilicity and heightened rebinding selectivity (IF = 2.42) of filter membranes was provided using two functional monomers (methacrylate and acrylamide), and microfiltration-grade composite membranes were generated by adjusting the imprinting polymerization time. The combination of the selective filter membranes and the syringe filter devices can effectively simplify the operation process, minimize the extraction time and reduce the tested sample volume. The method was validated by coupling with ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) and obtained a good correlation (r2 > 0.99). The limit of detection (LOD) of three analytes was 0.0800–0.6583 µg kg−1 and the mean recovery ranged from 85.5% to 91.2% within relative standard deviations (RSDs) less than 8.2%. Finally, an effective MIMFMs-UHPLC-MS/MS method was established for the recognition and detection of three amphenicol antibiotics in milk samples. The MIMFMs filtration technique offered in this work provides valuable science references and potential application prospects for complicated sample pretreatment.

Inhibition of OAT1/3 and CMPF uptake attenuates myocardial ischemia-induced chronic heart failure via decreasing fatty acid oxidation and the therapeutic effects of ruscogenin

Chronic heart failure (CHF) as a long-term disease is highly prevalent in elder people worldwide. Early diagnosis and treatments are crucial for preventing the development of CHF. Herein, we aimed to identify novel diagnostic biomarker, therapeutic target and drug for CHF. Untargeted metabolomic analysis has been used to characterize the different metabolomic profile between CHF patients and healthy people. Meanwhile, the targeted metabolomic study demonstrated the elevation of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) in the serum of CHF patients and coronary artery ligation-induced CHF mice. Subsequently, we firstly observed that elevation of CMPF impaired cardiac function and aggravated myocardial injury by enhancing fatty acid oxidation (FAO). Interestingly, inhibition of responsible transporters organic anion transporter 1/3 (OAT1/3) has been found to decrease the CMPF level, and suppress FAO-related key protein expressions including peroxisome proliferator-activated receptor alpha, peroxisome proliferative activated receptor-α, carnitine palmitoyl transferase 1, and malonyl CoA decarboxylase in coronary artery ligation-induced CHF mice. Meanwhile, the inhibitor of OAT1/3 presented an excellent improvement in cardiac function and histological injury. Based on the above findings, molecular docking was adopted to screen the potential therapeutic drug targeting OAT1/3, and ruscogenin (RUS) exhibited a great binding affinity with OAT1 and OAT3. Next, it was verified that RUS could remarkedly decrease the expression of OAT1/3 and CMPF levels in heart tissue of CHF mice, as well as suppress the expression of FAO-related proteins. What's more, RUS can effectively improve cardiac function, myocardial fibrosis and morphological damage. Collectively, this study provided a potential metabolic marker CMPF and novel target OAT1/3 for CHF, which were demonstrated to be involved in FAO. And RUS was identified as a potential anti-FAO drug for CHF by regulating OAT1/3.

Synthesis, characterization and molecular docking study of pyrazolines synthesized from chalcones: Antioxidant and acetylcholinesterase activities

Pyrazolines are heterocyclic compounds with nitrogen-containing rings, known mainly for their pharmacological potential. In recent times, much attention has been paid to the synthesis of these compounds to discover a wide spectrum of biological activities. Therefore, thirteen pyrazoline derivatives were synthesized from a cyclization reaction between chalcones and phenylhydrazines and showed total yields of 56 - 90%. All compounds were fully characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H and 13C NMR), and gas chromatography/mass spectrometry (GC/MS). Compounds were submitted to antioxidant activity using DPPH assay and acetylcholinesterase tests. It was observed that different substituents on the A and B rings of the pyrazolines have an influence on the antioxidant activity. Compounds 3, 7, 11 and 13 showed good activity with IC50 0.4017, 0.2892, 0.1100 and 0.0578, respectively. In the acetylcholinesterase enzyme inhibition assay, compounds 8 and 9 showed very good inhibition, similar to the used standards. The synthesized compounds that were shown to be active in the in vitro assay of acetylcholinesterase inhibition were investigated and subjected to molecular docking studies, and the results obtained showed great binding affinity and the best pose for compounds 3-(4-bromophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole (6) and 3-(4-chlorophenyl)-5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (8), according to the results experimental.

Inhibitory potential of phytochemicals on five SARS-CoV-2 proteins: in silico evaluation of endemic plants of Bosnia and Herzegovina

The outbreak of the coronavirus disease 2019, caused by the SARS-CoV-2 virus, has prompted global health concerns. In response, researchers have been conducting investigations on active compounds in plants that may hold the potential to inhibit the proliferation of the virus. The aim of this study was to simulate and predict structural interactions of selected compounds isolated from 28 endemic plants of Bosnia and Herzegovina against the main protease (Mpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), spike glycoprotein and uridylate-specific endoribonuclease (NendoU) of SARS-CoV-2. The majority of compounds, especially hesperidin, showed great binding affinity to the target proteins. The highest affinity for Mpro was observed for genistein and hesperidin, while in terms of structural interactions, both compounds achieved interactions of interest. Hesperidin and luteolin were the compounds with the highest binding affinity for PLpro, but no significant interactions were observed. For RdRp, hesperidin and quercetin showed the highest binding affinity, where both compounds formed interactions of interest. Hesperidin and fisetin were the compounds with the highest binding affinity for spike glycoprotein, and both compounds achieved significant interactions. The highest affinity for NendoU was obtained for hesperidin and isorhamnetin, where both compounds formed interactions of interest. Although these findings appear encouraging, further research is needed, which includes in vitro and in vivo assessments, along with clinical trials, to provide evidence for the potential therapeutic uses of these plants.