Receptor Sites Research Articles

Prediction, Design, Synthesis, Insecticidal Activities of Polysubstituted Pyridine Anthranilic Amide Derivatives

Based on the predicted structure, a series of polysubstituted pyridine compounds containing 5-(furan-2-yl)-1H-pyrazole-3-carboxamido were designed and synthesized. These compounds were characterized using 1H NMR, 13C NMR, 19F NMR and HRMS. The results of the bioassays indicated that certain compounds exhibited promising activities against Mythimna separata and Plutella xylostella. It is noteworthy that compound I-6 exhibited 47% insecticidal activity at a concentration of 0.01 μg/mL, which reached the same activity level as chlorantraniliprole (CHL).Moreover, the cytotoxicity experiment showed compound I-26 demonstrated 50% larvicidal activity against M. separata at 10 μg/mL. Moreover, the toxicity of I-26 (IC50 0.007365 μg/mL) was superior to that of CHL (IC50 1.059 μg/mL). Furthermore, molecular docking was employed to predict the binding positions of the compounds, which demonstrated a good correlation between their insecticidal activities and their binding values. Finally, DFT calculations and molecular docking were employed to refine the binding sites of the ryanodine receptors in M. separata with CHL and I-24. The research laid a foundation for the innovation of RyR insecticides in the future.

Experimental and theoretical vibrational analysis, structural conformations, DFT estimations, antibacterial, antifungal, DPPH,H2O2, Nitric oxide scavenging activity drug, in silico molecular docking, and ADMET studies of N-(2-carboxylphenyl) phthalimide (CPPD)

The title compound N-(2-carboxylphenyl) phthalimide (CPPD)was purchased with a stated purity of 99 % from M/S. Sigma-Aldrich Co. and utilized as such with no additional purification,CPPD is a thalidomide based derivative, which have led to the uses of most important drugs from 1950 and their mechanisms of action is essential for a better understanding of molecular targets with broad spectrum of biological activity. The obtained FTIR spectral data of the compound were compared to harmonic vibrational frequencies calculated using the ab initio DFT (B3LYP) technique with 6–311++G (d,p)basis sets. Furthermore, 13C and 1H NMR, first-order hyperpolarizability (βo) associated parameters (π, αo)of the compound, theSubsequent to recording the molecule’sUV–Visible spectra, DFT was used to analyze its electronic characteristics, including its HOMO and LUMO energies, molecular electrostatic potential (MESP), and Mulliken population studies were using ab initio DFT6-311++G (d,p)basis sets. Pharmacological Screening investigation of the title molecule showed a strong broad-spectrum of antifungal and antibacterial activity against various Gram (+) and Gram (−) bacteria using Ciprofloxacin as a positive control. The headline molecule is subjected toIn-silico molecular docking research with the purpose of improved recognize its biological activities, in addition with the minimal binding energy and hydrogen bond interaction that can view by Discovery Studio 4.0 visualizers. and drug likeness using Swiss ADME predictor (http://www.swissadme.ch/index.php) along with AdmetSAR-2.0 online software analysis tools features were investigated. The compound CPPD’s ability to degrade DPPH increased as a dose-dependent manner, with its maximal DPPH scavenging characteristic spanning from (18.2 ± 1.5 % to 73.2 ± 1.7 %) and maximum H2O2 scavenging trait ranging from (35.5 ± 5.3to 88.8 ± 3.1 %). The NO free radical scavenging property is linearly dependent on CPPD concentration. The interaction between the CPPD ligands and the 1HD2 protein is demonstrated by these data, as the protein displays a reduced binding energy value of −7.3 (Kcal/mol) and an inhibitory constant (ki) value of 4.39 μM. In swiss ADME prediction, CPPD is an evident from the physicochemical data that has an efficient receptor site binding mechanism. The lipophilicity of a drug is determined by its partition coefficient (Log P=log Po/w) between water and N-(2-carboxylphenyl) phthalimide. The paper further explains that the title compound can act as promising antibacterial and antioxidant agent throughin-vitro and molecular docking studies.

A statistical physics-based physicochemical study of L-phenylalanine adsorption on activated carbon.

In this comparative study of the adsorption of L-phenylalanine (L-Phe) on two modified low-activated carbons (ACK and ACZ) at four temperatures (293-313K), steric and energetic characteristics of adsorption were investigated. An advanced statistical physics multilayer model involving single-layer and double-layer adsorption scenarios was developed to interpret the L-Phe adsorption phenomenon. Modeling results indicate that two and three L-Phe layers were arranged depending on the tested adsorption systems. The estimated number of L-Phe molecules per leading adsorption site varied from 1.71 to 2.09 and from 1.76 to 1.86 for systems L-Phe-ACK and L-Phe-ACZ, respectively. The results show that a multimolecular adsorption mechanism might connect this amino acid molecule on ACZ and ACK surfaces in a non-parallel location. These parameters changed as follows, according to the adsorbed quantity at saturation analysis: Qasat (L-Phe-ACK) ˃ Qasat (L-Phe-ACZ). This indicates that ACK material was more efficient and valuable for L-Phe adsorption than ACZ. It was also shown that the adsorption capacity decreases as the temperature increases, proving the exothermicity of the adsorption process. This analytical substantiation is confirmed by calculating the binding energies, suggesting the occurrence of physical bonds between L-Phe amino acid molecules and ACK/ACZ binding sites and among L-Phe-L-Phe molecules. Pore size distribution was interpreted and calculated by applying the Kelvin theory to data from single adsorption isotherms. All used temperatures depicted a distribution of pores below 2nm. The docking analysis involving L-Phe and the ACZ and ACK adsorbents reveal a significant resemblance in how receptors detect ligands. Consequently, the findings from the docking process confirm that the calculated binding affinities fall within the spectrum of adsorption energy. This study analyzed the adsorption capacity of the L-Phe through a model proposed by statistical physics formalism. Molecular docking was used to determine the various types of interactions between the two activated carbons. Two aspects, including orientation of L-Phe on the site, number of molecules per site n, interaction energy, density of receptor site, and adsorption capacity, were discussed to elucidate the influence of activation on the two adsorbents.

Synthesis, biological and computational evaluation of benzoxazole hybrid analogs as potential anti-Alzheimer's agents.

Aim: Current study aims exploration of bis-benzoxazole bearing bis-Schiff base scaffolds (1-16) as anti-Alzheimer's agents.Materials & methods: 2-aminophenol is used as starting materials which react with different reagents in different step to give us bis-benzoxazole bearing bis-Schiff base analogs. NMR and HREI-MS techniques were used for characterization. All derivatives demonstrated varied range of activities with IC50 values 1.10±0.40-24.50±0.90μM against acetylcholinesterase (AChE) and 1.90±0.70-28.60±0.60μM against butyrylcholinesterase (BuChE) in contrast to donepezil. In both cases, analog-3 was found most potent. Molecular docking explored modes of interactions between scaffolds and receptor sites of targeted enzymes.Conclusion: This study offering promising approach for optimization and development of potent inhibitors of cholinesterase enzymes.

Novel neuropharmacological activity of citrus lime (Citrus aurantifolia): A standardized lime peel supplement enhances non-rapid eye movement sleep by activating the GABA type A receptor

Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABAA receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABAA receptor and directly activated the GABAA receptors. The hypnotic effects and GABAA receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABAA receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABAA receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic.

Exploring the potential of nanoparticles as a drug delivery system for cancer therapy: A review

In this review, we discuss the use of organic nanoparticles such as liposomes, polymeric nanoparticles, dendrimers, and inorganic nanoparticles such as gold nanoparticles and mesoporous silica nanoparticles in drug delivery in chemotherapy for cancer therapy. Another strategy is the use of nanoparticle vehicles for drug delivery through the natural openings on tumor vessels called fenestrations. Both of these can be functionalized to attach angiotensin to lymphocytes or any certain part of the cancer cell membrane, microenvironment, or cytoplasmic or nuclear receptor sites, and therefore a high concentration of drug delivery to targeted cancer cells is achieved, but with less or no toxicity to normal tissue. The potential advantages evident in this technology are useful approaches to established high-concentration drug treatment of cancer tissues without harming normal cells. Some features of a nanoparticle-based drug delivery system include the durability of the vehicle, biocompatibility, permeation, and ability to target specific types of cells. Organic and inorganic nanoparticles have developed this kind of drug-carrier system. Particulate systems are also still being explored for cancer drug resistance mechanisms, and their function in immunotherapy is expanding.

In Silico and In Vitro Evaluation of Bioactive Compounds of Vallisneria spiralis L. against Candida albicans

Background This study focused on the extraction, isolation, characterization, and molecular docking of phytochemicals from Vallisneria spiralis L. to determine its antifungal activity. Natural products and structural analogs have always played an important role in pharmacotherapy, particularly in the treatment of infections and malignancies. Methods Vallisneria spiralis L. leaves were pulverized into a fine powder and extracted using a Soxhlet apparatus, and the crude chloroform extract was separated by flash column chromatography. Thin-layer chromatography was used to assess the obtained fractions. Infrared spectra were obtained using a Perkin Elmer spectrometer. NMR spectra were collected using a Bruker spectrometer. Qualitative phytochemical investigations were performed to identify compounds in the extracts. The susceptibility of the test compound to Candida albicans was assessed using disk diffusion. A docking study was conducted to dock the three-dimensional structures of the extracted phytocompounds of Vallisneria spiralis L. into the receptor site of the target proteins using Autodock software. MD simulations were used to study the dynamic behavior, conformational changes, and stability of the proteins using the top three hit chemicals. Results These results suggest that Vallisneria spiralis L. extract contains various phytoconstituents, including carbohydrates, tannins, flavonoids, steroids, terpenoids, and glycosides. The distinctive functional groups of the extract were identified using a Fourier-Transform Infrared (FTIR) spectrophotometer. Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the structures of the isolated and purified extracts. The antifungal activity of Vallisneria spiralis L. extract against Candida albicans was found to be significantly stronger at a concentration of 200 mg/mL. Conclusion The findings of the study were obtained using in vitro and in silico methods to investigate the antifungal effect of Vallisneria spiralis L., which highlighted it as a potential natural antifungal treatment for Candida infection, which could be further investigated.

A novel vesicular stomatitis virus armed with IL-2 mimic for oncolytic therapy

Oncolytic virus (OV) is increasingly being recognized as a novel vector in cancer immunotherapy. Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment, so called transformation of ‘cold’ tumors into ‘hot’ tumors. The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators. The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15. However, it specifically lacks the binding site of IL-2 receptor α subunit (CD25), therefore unable to induce the Treg proliferation. In present study, a recombinant vesicular stomatitis virus expressing the Neo-2/15 (VSVM51R-Neo-2/15) was generated. Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic. Moreover, treatment with VSVM51R-Neo-2/15 increased the number of activated CD8+ T cells but not Treg cells in tumors. More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment, and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity. In addition, combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response. These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors, providing promising attempts for further clinical trials.

Non-targeted metabolomics reveals the characteristics of the unique bitterness substances in quinoa

Bitterness is a key factor that affects the consumption of quinoa products, even if they are nutritious. In this study, a non-targeted metabolomics approach based on UHPLC-Orbitrap-MS was applied to comprehensively profile the characteristic metabolites of twenty-two quinoas. A total of twenty key metabolites were identified correlated with bitterness, among which, fifteen were triterpenoid saponins. In addition, these metabolites bind to the active site of the human bitter taste receptor and are the main compounds that produce the bitter taste of quinoa. Our results contribute to a deeper understanding of the origin of quinoa bitterness and provide directions for optimizing its flavor to improve market acceptance.

Lanthanide metal-organic framework functionalized with 10-hydroxybenzo[h]quinoline for ratiometric sensing to real-time determine monophenolase activity through indicator displacement assay

Tyrosinase monophenolase activity plays a crucial role in various biological processes and industrial applications, making the development of continuous monophenolase assays highly significant. In this study, ratiometric fluorescence sensing using a dual-emission sensor was established to determine monophenolase activity in real-time by integrating indicator displacement assay with lanthanide metal-organic frameworks (MOFs). Europium MOFs functionalized with 10-hydroxybenzo[h]quinoline (HBQ) were fabricated by conjugating an HBQ guest fluorophore to the 3,5-dicarboxyphenylboronic acid (DBA) ligand using a solvothermal method. The conjugated HBQ served as an optical indicator at 510 nm with large Stokes shift, whereas the Eu-MOFs acted as a fluorescent internal standard at 616 nm for dual emission. DBA acts as an antenna ligand and provides a competitive receptor site for L-3,4-dihydroxyphenlalanine (L-DOPA) and HBQ. L-DOPA competitively binds to DBA owing to its higher affinity and displaces the conjugated HBQ, resulting in the quenching of HBQ and Eu-MOFs fluorescence. A linear change in the dual-emission intensity ratio was observed as a ratiometric response towards L-DOPA. The sensor quantified L-DOPA with a detection limit of 0.13 μM. Monophenolase activity was correlated with the real-time change in the ratiometric signal using L-DOPA as the product of the enzymatic reaction. A progression curve for the formation of L-DOPA was constructed to calculate the initial rate, yielding a low detection limit for monophenolase activity of 0.15 U·mL−1. The method has been successfully applied to real samples, kinetic studies, and high-throughput screening of inhibitors. This sensing platform opens a new avenue for determining tyrosinase activity.

Synthesis and nootropic activity prediction of some 4-(aminomethyl)-1-benzylpyrrolidin-2-one derivatives structurally related with nebracetam

The aim. Search for new biologically active substances with improved nootropic parameters among analogues of 4-(aminomethyl)-1-benzylpyrrolidine-2-one (Nebracetam). Materials and methods. The required reagents were purified using standard techniques. The elemental analysis was performed on a "Hewlett Packard" automatic analyzer M-180 company. 1H NMR spectra were recorded on Varian Gemini 400 MHz spectrometer in DMSO-d6 as a solvent. LC/MS spectra were recorded with a PE SCIEX API 150EX liquid chromatograph equipped. The Autodock 4.2 software package was used for molecular docking. The active centers of the peptides (PDB ID: 5CXV, 6PV7) was used as the biologycal targets. Results and discussion. Basic and alternative methods (1 and 2) of obtaining were used to synthesise target analogues of 4-(aminomethyl)-1-R-benzylpyrrolidine-2-one. As a result of synthetic studies, an optimized method with an alternative method has been proposed. The advantages include reducing the duration and number of synthesis stages and avoiding the use of sodium azide, a highly toxic and hazardous substance. Molecular docking of the synthesized compounds at well-documented acetylcholine receptor sites indicates that all tested molecules will contribute to the manifestation of nootropic activity to varying degrees through cholinergic neurotransmission mechanisms. This is evidenced by the calculated docking values in relation to the muscarinic target. According to the docking results, it was found that depending on the enantiomeric configuration, the molecules formed stable complexes with the target and had characteristic binding modes both in the orthosteric site and in the extracellular vestibule (site of positive allosteric modulation of mAChR). It indicates the prospects of modifying the "nebracetam scaffold" at the phenyl fragment with halogen substituents. Conclusions. An effective method for synthesising analogues of 4-(aminomethyl)-1-R-benzylpyrrolidin-2-ones has been developed. The molecular docking revealed potential mechanisms of nootropic action of the synthesized derivatives as potential agonists and positive allosteric modulators of the muscarinic receptor

Statistical physics of azo reactive dye adsorption by metal hydroxide sludge for water remediation

We performed a theoretical investigation of azo reactive red (RR-120) on metal hydroxide sludge (MHS) using five advanced statistical physics models to interpret thermodynamic equilibrium data for potential water remediation applications. Each model incorporates multiple physicochemical parameters to comprehensively describe the microscopic process through empirical data fitting. The thermodynamic functions (entropy, internal energy and Gibbs free energy) were analyzed using the grand canonical formalism. Our analysis indicated that the single-energy monolayer model represents the most realistic scenario. The adhesion of RR-120 onto MHS was endothermic with an adsorption energy below 40.0 kJ/mol suggesting that Van der Waals interactions and hydrogen bonding are the predominant driving forces. The stereographic analysis demonstrated that as the density of receptor sites (Nm) incremented, there was a corresponding decline in the number of anchored entities per site (n). Moreover, thermodynamic assessment revealed that the disorder increased before half-saturation and decreased after half-saturation while negativity of Gibbs free energy indicated a spontaneous process of RR-120 adsorption in all tested temperatures. The exceptional adsorption capabilities of MHS will open up new avenues in wastewater treatment, soil remediation and air purification.

Experimental and Mathematical Investigation of Hydrogen Absorption in LaNi5 and La0.7Ce0.1Ga0.3Ni5 Compounds

In the present study, the hydrogen-absorption properties of the LaNi5 and the La0.7Ce0.1Ga0.3Ni5 compounds were determined and compared. This work is therefore divided into two parts: an experimental part that presents and discusses the kinetics and isotherms of hydrogen absorption in the two compounds at two different temperatures (298 K and 318 K). In addition, the temperature variations inside the hydride bed were determined. In the second section, the experimental isotherms were compared to a numerical model processed using statistical physics. Following that, thanks to the perfect agreement between the experimental data and the proposed model, the stereographic and energetic parameters associated with the hydrogen absorption reaction, such as the number of hydrogen atoms per receptor site (n1, n2), the densities of the sites (Nm1, Nm2), the half-saturation pressures (P1, P2) and the absorption energies (ΔE1, ΔE2) for each receptor site, were calculated. All of these parameters are acquired by making numerical adjustments to the experimental data. Thermodynamic functions, such as internal energy and Gibbs energy, which regulate the absorption process, were then identified using these parameters. For both compounds, all of the aforementioned were compared and discussed in relation to initial temperature and pressure. The results demonstrated that the hydrogen-storage properties in LaNi5 are enhanced by more than 30% of stored mass and kinetics when Ce and Ga are substituted at the La sites.

Assessing anti oxidant, antidiabetic potential and GCMS profiling of ethanolic root bark extract of Zanthoxylum rhetsa (Roxb.) DC: Supported by in vitro, in vivo and in silico molecular modeling.

Zanthoxylum rhetsa (ZR) is used traditionally to manage a variety of ailments, including diabetes. Oxidative stress may accelerate the diabetic condition. The available antidiabetic and antioxidant drugs have many shortcomings including resistance, inefficiency, higher dose, side effects and costs. The goal of the current investigation was to assess the antioxidant capacity and antidiabetic activity of an ethanolic extract of Zanthoxylum rhetsa root bark (ZRRB) through in vitro, in vivo, and in silico methods. The antioxidant capacity of the ZRRB extract was measured using both the DPPH radical assay and the total antioxidant activity test. The oral glucose tolerance test (OGTT) and alloxan-induced diabetic mice model were also used to examine in vivo antidiabetic efficacy. Phytochemicals identification was done by GCMS analysis. Additionally, computational methods such as molecular docking, ADMET analysis, and molecular dynamics (MD) modeling were performed to determine the above pharmacological effects. The extract demonstrated significant DPPH scavenging activity (IC50 = 42.65 μg/mL). In the OGTT test and alloxan-induced diabetes mice model, the extract effectively lowered blood glucose levels. Furthermore, in vitro inhibition of pancreatic α-amylase studies demonstrated the ZRRB extract as a good antidiabetic crude drug (IC50 = 81.45 μg/mL). GCMS investigation confirmed that the crude extract contains 16 major phytoconstituents, which were docked with human peroxiredoxin-5, α-amylase, and sulfonylurea receptor 1. Docking and pharmacokinetic studies demonstrated that among 16 phytoconstituents, 6H-indolo[3,2,1-de] [1,5]naphthyridin-6-one (CID: 97176) showed the highest binding affinity to targeted enzymes, and imitated Lipinski's rule of five. Furthermore, MD simulation data confirmed that the aforementioned compound is very steady to the binding site of α-amylase and sulfonylurea receptor 1 receptors. Findings from in vitro, in vivo and in silico investigation suggest that ZRRB extract contains a lead compound that could be a potent source of antidiabetic drug candidate.

Identification of small molecule inhibitors of the Chloracidobacterium thermophilum type IV pilus protein PilB by ensemble virtual screening

Antivirulence strategy has been explored as an alternative to traditional antibiotic development. The bacterial type IV pilus is a virulence factor involved in host invasion and colonization in many antibiotic resistant pathogens. The PilB ATPase hydrolyzes ATP to drive the assembly of the pilus filament from pilin subunits. We evaluated Chloracidobacterium thermophilum PilB (CtPilB) as a model for structure-based virtual screening by molecular docking and molecular dynamics (MD) simulations. A hexameric structure of CtPilB was generated through homology modeling based on an existing crystal structure of a PilB from Geobacter metallireducens. Four representative structures were obtained from molecular dynamics simulations to examine the conformational plasticity of PilB and improve docking analyses by ensemble docking. Structural analyses after 1 μs of simulation revealed conformational changes in individual PilB subunits are dependent on ligand presence. Further, ensemble virtual screening of a library of 4234 compounds retrieved from the ZINC15 database identified five promising PilB inhibitors. Molecular docking and binding analyses using the four representative structures from MD simulations revealed that top-ranked compounds interact with multiple Walker A residues, one Asp-box residue, and one arginine finger, indicating these are key residues in inhibitor binding within the ATP binding pocket. The use of multiple conformations in molecular screening can provide greater insight into compound flexibility within receptor sites and better inform future drug development for therapeutics targeting the type IV pilus assembly ATPase.

Investigation of propranolol hydrochloride adsorption onto pyrolyzed residues from Bactris guineensis through physics statistics modeling

In this study, PROP adsorption was investigated using activated carbon derived from Bactris Guineensis residues and physical statistical modeling. The characterization results indicate high specific surface areas (624.72 and 1125.43 m2 g−1) and pore diameters (2.703 and 2.321 nm) for the peel and stone-activated carbon, respectively. Adsorption equilibrium was investigated at different temperatures (298 to 328 K), and it was found that the adsorption capacity increased with temperature, reaching maximum values of 168.7 and 112.94 mg g−1 for the peel and stone-activated carbon, respectively. The application of physical statistical modeling indicates that a monolayer model with one energy site is adequate for describing both systems, with an R2 above 0.986 and a low BIC of 20.021. According to the steric parameters, the density of molecules per site tends to increase by 116.9% for the stone and 61.6% for the peel. In addition, the model indicates that the number of molecules decreases with increasing temperature from 1.36 to 0.81 and from 1.03 to 0.82. These results indicate that temperature controls the number of receptor sites and the orientation in which propranolol is adsorbed at the surface. The adsorption energies were similar for both systems (approximately 10 kJ mol−1), which indicates that the adsorption occurred due to physical interactions. Finally, the application of thermodynamic potential functions indicates that the maximum entropy is reached at concentrations of half-saturation (Ce 3.85 and 4.6 mg L−1), which corresponds to 1.60 × 10–18 and 1.86 × 10–18 kJ mol−1 K−1 for the stone and peel, respectively. After this point, the number of available sites tends to decrease, which indicates the stabilization of the system. The Gibbs energy tended to decrease with increasing concentration at equilibrium, reaching minimum values of − 1.73 × 10–19 and − 1.99 × 10–19 kJ mol−1, respectively. Overall, the results obtained here further elucidate how the adsorption of propranolol occurs for different activated carbons from the same source.

The Structural Basis for Recognition of Human Leukocyte Antigen Class I Molecules by the Pan-HLA Antibody W6/32.

The central immunological role of HLA class I (HLA-I) in presenting peptide Ags to cellular components of the immune system has been the focus of intense study for >60 y. A confounding factor in the study of HLA-I has been the extreme polymorphism of these molecules. The mAb W6/32 has been a fundamental reagent bypassing the issue of polymorphism by recognizing an epitope that is conserved across diverse HLA-I allotypes. However, despite the widespread use of W6/32, the epitope of this Ab has not been definitively mapped. In this study, we present the crystal structure of the Fab fragment of W6/32 in complex with peptide-HLA-B*27:05. W6/32 bound to HLA-B*27:05 beneath the Ag-binding groove, recognizing a discontinuous epitope comprised of the α1, α2, and α3 domains of HLA-I and β2-microglobulin. The epitope comprises a region of low polymorphism reflecting the pan-HLA-I nature of the binding. Notably, the W6/32 epitope neither overlaps the HLA-I binding sites of either T cell Ag receptors or killer cell Ig-like receptors. However, it does coincide with the binding sites for leukocyte Ig-like receptors and CD8 coreceptors. Consistent with this, the use of W6/32 to block the interaction of NK cells with HLA-I only weakly impaired inhibition mediated by KIR3DL1, but impacted HLA-LILR recognition.

Computational scrutiny of psychoactive cannabinoids through molecular electrostatic potential and CB1 receptor interaction

Delta-9-THC and psychoactive derivatives were scrutinized with molecular electrostatic potential (MEP) and ligand-CB1 interaction. At the B3LYP/6-31G** level, MEP maps of the most active cannabinoids (mac), pKi ≥ 6.72 (1-13), revealed that the directional orientation of the lone pair of electrons in the phenolic OH, in general, produces a greater interaction with the substituent at position C9, orienting the carbocyclic ring system, reflecting the psychoactivity of the compounds. In addition, the existence of the side alkyl chain contributes to improving this property. In less active cannabinoids (lac), pKi < 6.72 (14-22), the negative MEP shows a more spread out, “diluted” electron density, probably due to the orientation of the carbocyclic ring system unfavorable to the pharmacophoric conformation. Furthermore, the MEP maps show cannabinoids 14-22 presenting small differences in the distribution of this density, when compared to 1-13, which seems crucial to the decrease in psychoactivity. When examining the ligand-CB1 interaction, the orientations of the compounds were shown to be governed basically by the hydrophobic pockets between helices III, IV, VI, and VII; with the most active alkyl fragment (1-13) directed to the hydrophobic site, the nonpolar fragment (methylcyclohexene) to the hydrophobic pocket, the phenolic OH to the hydrophilic pocket and the oxane fragment oriented to a small hydrophilic pocket of CB1. In the lac (14-22), the poses of the substituents COOH (14), COOCH3 (16), and COCH3 (22) were oriented towards a hydrophobic pocket and 15, 17, 18, and 21 presented the oxygenated groups directed to the hydrophilic sites of the CB1 receptor. The OH substituent in 19 directs it to the hydrophobic pocket and 20, with the OH group but distant from phenolic OH, presents said group also directed to this hydrophobic pocket of CB1. The scrutiny of cannabinoids with MEP and the ligand-CB1 interaction could guide the design of new molecules with better psychoactivity.

A Systematic Review on Sedative and Hypnotics

Abstract: Sedative and hypnotic drugs are central nervous system depressants primarily used to induce calmness, reduce anxiety, and promote sleep. These medications include benzodiazepines, barbiturates, and various non-benzodiazepine sleep aids, each varying in their mechanism of action, efficacy, and safety profiles. Benzodiazepines, such as diazepam and alprazolam, enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA-A receptor, resulting in sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. They are commonly prescribed for anxiety disorders, insomnia, seizures, and muscle spasms. However, their use is associated with risks of tolerance, dependence, and withdrawal symptoms. Barbiturates, such as phenobarbital, were once widely used for their sedative and hypnotic properties but have largely been replaced by benzodiazepines and other safer alternatives due to their higher risk of overdose and dependence. Barbiturates enhance GABAergic transmission but also directly activate GABA receptors, leading to more profound central nervous system depression. Non-benzodiazepine sleep aids, including drugs like zolpidem, eszopiclone, and zaleplon, act on the benzodiazepine receptor site but have a different chemical structure. These drugs are often preferred for short-term treatment of insomnia due to their relatively lower risk of dependence and adverse effects compared to benzodiazepines.

B cell epitope mapping: The journey to better vaccines and therapeutic antibodies

B-cell epitope mapping is an approach that can identify and characterise specific antigen binding sites of B-cell receptors and secreted antibodies. The ability to determine the antigenic clusters of amino acids bound by B-cell clones provides unprecedented detail that will aid in developing novel and effective vaccine targets and therapeutic antibodies for various diseases. Here, we discuss conventional approaches and emerging techniques that are used to map B-cell epitopes.