Journal of Molecular Recognition最新文献

COVID-19 was a global pandemic in the year 2020. Several treatment options failed to cure the disease. Thus, plant-based medicines are becoming a trend nowadays due to their less side effects. Bioactive chemicals from natural sources have been utilised for centuries as treatment options for a variety of ailments. To find out the potent bioactive compounds to counteract COVID-19, we use systems pharmacology and cheminformatics. They use the definitive data and predict the possible outcomes. In this study, we collected a total of 72 phytocompounds from the medicinally important plants such as Garcinia mangostana and Cinnamomum verum, of which 13 potential phytocompounds were identified to be active against the COVID-19 infection based on Swiss Target Prediction and compound target network analysis. These phytocompounds were annotated to identify the specific human receptor that targets COVID-19-specific genes such as MAPK8, MAPK14, ACE, CYP3A4, TLR4 and TYK2. Among these, compounds such as smeathxanthone A, demethylcalabaxanthone, mangostanol, trapezifolixanthone from Garcinia mangostana and camphene from C. verum were putatively target various COVID-19-related genes. Molecular docking results showed that smeathxanthone A and demethylcalabaxanthone exhibit increased binding efficiency towards the COVID-19-related receptor proteins. These compounds also showed efficient putative pharmacoactive properties than the commercial drugs ((R)-remdesivir, favipiravir and hydroxychloroquine) used to cure COVID-19. In conclusion, our study highlights the use of cheminformatics approach to unravel the potent and novel phytocompounds against COVID-19. These phytocompounds may be safer to use, more efficient and less harmful. This study highlights the value of natural products in the search for new drugs and identifies candidates with great promise.

β-Lactoglobulin (BLG) is a member of the lipocalin family. As other proteins from this group, BLG can be modified to bind specifically compounds of medical interests. The aim of this study was to evaluate the role of two mutations, L39Y and L58F, in the binding of topical anesthetic pramoxine (PRM) to β-lactoglobulin. Circular dichroism spectroscopy, isothermal titration calorimetry (ITC), and X-ray crystallography were used to understand the mechanisms of BLG–PRM interactions. Studies were performed for three new BLG mutants: L39Y, L58F, and L39Y/L58F. ITC measurements indicated a significant increase in the affinity to the PRM of variants L58F and L39Y. Measurements taken for the double mutant L39Y/L58F showed the additivity of two mutations leading to about 80-fold increase in the affinity to PRM in comparison to natural protein BLG from bovine milk. The determined crystal structures revealed that pramoxine is accommodated in the β-barrel interior of BLG mutants and stabilized by hydrophobic interactions. The observed additive effect of two mutations on drug binding opens the possibility for further designing of new BLG variants with high affinity to selected drugs.

This research shows the exact detection of riboflavin (RF), dopamine (DA), and L-tryptophan (Trp) through molecularly imprinted polymer (MIP) based on the electropolymerization method. MIP was placed on the surface of the glassy carbon electrode (GCE) by electropolymerization of monomers such as catechol and para-aminophenol, in the presence of all three analytes. The introduced sensor was investigated using field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), Fourier-transform infrared spectroscopy (FTIR), and electrochemical methods, for example, electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and differential pulse voltammetry (DPV). The MIP/GCE performs well in terms of selectivity, reproducibility, repeatability, and stability. This sensor revealed good linear ranges of 0.005–500 μM for RF, 0.05–500 μM for DA, and 0.1–250 μM for Trp with limits of detection (LOD) as 0.0016 μM, 0.016 μM, and 0.03 μM for RF, DA, and Trp, respectively. The modified GCE was successfully applied to detect RF, DA, and Trp in serum and milk samples with satisfactory results.

The green production of silver nanoparticles (AgNPs) produces AgNPs with minimum influence on the environment by using plant components such as alkaloids, carbohydrates, lipids, enzymes, flavonoids, terpenoids, and polyphenols as reducing agents. In the present investigation, Azadirachta indica leaf extract was used to form AgNPs from a 1 mM silver nitrate solution. The plan proved to be incredibly straightforward, cost-effective, and effective. The production of the nanoparticles was observed visually, where the colorless fluid turns into a brown-colored solution. Further research was carried out using x-ray diffraction, Fourier-transform infrared analysis, scanning electron microscopy, and transmission electron microscopy (TEM) in addition to UV–visible spectroscopy. The size range of AgNPs determined by TEM was 10–30 nm. When the diffusion technique was employed to demonstrate the antibacterial effect of AgNPs on various pathogens, the zones of inhibition for Staphylococcus aureus, Bacillus cereus, and Escherichia coli, when 50 g of AgNPs were used were 16, 12, and 17 mm, respectively. By examining the leakage of reducing sugars and proteins, the mechanism by which nanoparticle antibacterial properties were explored, showed that AgNPs were capable of lowering membrane permeability.

The interactions of the classic phytohormones gibberellic acid (gibberellin A₃, GA₃) and abscisic acid (dormin, ABA), which antagonistically regulate several developmental processes and stress responses in higher plants, with human placental glutathione S-transferase P1-1 (hpGSTP1-1), an enzyme that plays a role in endo- or xenobiotic detoxification and regulation of cell survival and apoptosis, were investigated. The inhibitory potencies of ABA and GA₃ against hpGSTP1, as well as the types of inhibition and the kinetic parameters, were determined by making use of both enzyme kinetic graphs and SPSS nonlinear regression models. The structural basis for the interaction between hpGSTP1-1 and phytohormones was predicted with the aid of molecular docking simulations. The IC₅₀ values of ABA and GA₃ were 5.3 and 5.0 mM, respectively. Both phytohormones inhibited hpGSTP1-1 in competitive manner with respect to the cosubstrates GSH and CDNB. When ABA was the inhibitor at [CDNB]_f–[GSH]_v and at [GSH]_f–[CDNB]_v, V_m, K_m, and K_i values were statistically estimated to be 205 ± 16 μmol/min-mg protein, 1.32 ± 0.18 mM, 1.95 ± 0.25 mM and 175 ± 6 μmol/min-mg protein, 0.85 ± 0.06 mM, 1.85 ± 0.16 mM, respectively. On the other hand, the kinetic parameters V_m, K_m, and K_i obtained with GA₃ at [CDNB]_f–[GSH]_v and at [GSH]_f–[CDNB]_v were found to be 303 ± 14 μmol/min-mg protein, 1.77 ± 0.13 mM, 3.38 ± 0.26 mM and 249 ± 7 μmol/min-mg protein, 1.43 ± 0.07 mM, 2.89 ± 0.19 mM, respectively. Both phytohormones had the potential to engage in hydrogen-bonding and electrostatic interactions with the key residues that line the G- and H-sites of the enzyme's catalytic center. Inhibitory actions of ABA/GA₃ on hpGSTP1-1 may guide medicinal chemists through the structure-based design of novel antineoplastic agents. It should be noted, however, that the same interactions may also render fetuses vulnerable to the potentially toxic effects of xenobiotics and noxious endobiotics.

Helicobacter pylori is the most common cause of gastric ulcers and is associated with gastric cancer. The enzyme HppA of class C nonspecific acid phosphohydrolases (NSAPs) of H. pylori plays a crucial role in the electron transport chain. Herein, we report an in silico homology model of HppA consisting of a monomeric α + β model. A high throughput structure-based virtual screening approach yielded potential inhibitors against HppA with higher binding energies. Further analyses of molecular interaction maps and protein–ligand fingerprints, followed by molecular mechanics-generalized Born surface area (MM-GBSA) end point binding energy calculations of docked complexes, resulted in the detection of top binders/ligands. Our investigations identified potential substrate-competitive small molecule inhibitors of HppA, with admissible pharmacokinetic properties. These molecules may provide a starting point for developing novel therapeutic agents against H. pylori.

The aim of this study was to investigate the inhibitory effects of some pesticides known to have harmful effects on human health on carbonic anhydrase isoenzymes. Therefore, carbonic anhydrase isoenzymes (hCA I and II) were purified from human erythrocytes. The isoenzymes were purified from human erythrocytes by using an affinity column that has the chemical structure of Sepharose-4B-4-(6-amino-hexyloxy)-benzenesulfonamide. The purity of the isoenzymes was checked by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDSPAGE). It was determined that the pesticides used in this study inhibit hCA I and hCA II isoenzymes at different levels in vitro. It was determined that the strongest inhibitor for the hCA I enzyme was Carbofuran (IC₅₀:6.52 μM; K_i: 3.58 μM) and the weakest one was 1-Naphtol (IC₅₀:16.55 μM; K_i: 14.4 μM) among these pesticides. It was also found that the strongest inhibitor for the hCA II enzyme was coumatetralil (IC₅₀:5.06 μM; K_i: 1.62 μM) and the weakest one was Dimethachlor (IC₅₀ 14.6 μM; K_i: 8.44 μM).

Cry11Aa and Cyt1Aa are two pesticidal toxins produced by Bacillus thuringiensis subsp. israelensis. To improve our understanding of the nature of their oligomers in the toxic actions and synergistic effects, we performed the atomic force microscopy to probe the surfaces of their natively grown crystals, and used the L-weight filter to enhance the structural features. By L-weight filtering, molecular sizes of the Cry11Aa and Cyt1Aa monomers obtained are in excellent agreement with the three-dimensional structures determined by x-ray crystallography. Moreover, our results show that the layered feature of a structural element distinguishes the topographic characteristics of Cry11Aa and Cyt1Aa crystals, suggesting that the Cry11Aa toxin has a better chance than Cyt1Aa for multimerization and therefore cooperativeness of the toxic actions.

As a natural carrier protein, zein was intensively studied for the construction of a flavonoid delivery system. Chrysin has presented superior tumor-resistant, anti-inflammatory, and anti-oxidation potentials among the flavonoid candidates in clinical practice. However, due to inadequate research, the binding mechanism and structural affinity of zein to chrysin are still indeterminate. Therefore, multispectral methods were employed to explore the molecular interaction of zein and chrysin in this work. These techniques showed that chrysin reduced the intrinsic fluorescence of zein via a static process and that the interaction between zein and chrysin was mainly driven spontaneously by hydrophobic forces. Additionally, the experimental results revealed the changed microenvironment in the vicinity of tyrosine and affected secondary structure in the presence of chrysin, indicating zein's conformation were altered by chrysin. This work provided comprehensive insight into the combination of plant-derived protein (zein) and flavonoids (chrysin) and helped rationalize the protection, transportation, and release of chrysin through a zein-based delivery system.

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease. Mature IL-17A is a homodimer that binds to the extracellular type-III fibronectin D1:D2-dual domain of its cognate IL-17 receptor A (IL-17RA). In this study, we systematically examined the structural basis, thermodynamics property, and dynamics behavior of IL-17RA/IL-17A interaction and computationally identified two continuous hotspot regions separately from different monomers of IL-17A homodimer that contribute significantly to the interaction, namely I-shaped and U-shaped segments, thus rendered as a peptide-mediated protein–protein interaction (PmPPI). Self-inhibitory peptides (SIPs) are derived from the two segments to disrupt IL-17RA/IL-17A interaction by competitively rebinding to the IL-17A-binding pocket on IL-17RA surface, which, however, only have a weak affinity and low specificity for IL-17RA due to lack of the context support of intact IL-17A protein, thus exhibiting a large flexibility and intrinsic disorder when splitting from the protein context and incurring a considerable entropy penalty when rebinding to IL-17RA. The U-shaped segment is further extended, mutated and stapled by a disulfide bridge across its two strands to obtain a number of double-stranded cyclic SIPs, which are partially ordered and conformationally similar to their native status at IL-17RA/IL-17A complex interface. Experimental fluorescence polarization assays substantiate that the stapling can moderately or considerably improve the binding affinity of U-shaped segment-derived peptides by 2–5-fold. In addition, computational structural modeling also reveals that the stapled peptides can bind in a similar mode with the native crystal conformation of U-shaped segment in IL-17RA pocket, where the disulfide bridge is out of the pocket for avoiding intervene of the peptide binding.