Ionic liquid-based technologies are promising both as antibacterial agents and in drug delivery, as they can improve drug solubility and capacity to bypass lipid bilayers while also taking advantage of ionic liquids' physical properties, such as negligible vapor pressure and stability. In both applications, it is imperative to understand how the molecular structure of the ionic liquid determines its interaction with cellular membranes. In this work, molecular dynamics simulations with coarse-grained models were applied to study the penetration of eight ionic liquids based on the 1,3-dialkyl-imidazolium cation with different alkyl group sizes into DPPC bilayers from both dilute and concentrated aqueous solutions. Potential of mean force calculations were performed to evaluate the thermodynamics of cation penetration, and graph theory was used to characterize their nonhomogeneous distributions inside the bilayers. Distinct effects were noticed over the bilayer morphology: Cations with a single small or medium alkyl tail do not induce significant changes over the bilayer structure, while cations with a 16-carbon-atom chain are water-insoluble and, in concentrated solutions, are capable of partially removing lipid molecules. Incorporated cations with two medium-sized tails remain close to the water interface, reducing the interaction between lipids and decreasing the bilayer thickness, while cations with two long tails penetrate into the hydrophobic center of the bilayer and increase its thickness instead. As a consequence of the different interactions, two distinct mechanisms have been proposed for the drug delivery action of ionic liquids, depending on their water solubility and clustering tendency.

Potential of tea polyphenols to ameliorate the quality of beef meatballs during frozen storage and its action mechanism.

Development of a Nano-toughened multifunctional composite hydrogel based on chitosan and its applications in catalytic and flexible sensors.

Hydrogel electrolytes have been widely utilized in flexible supercapacitors due to their excellent flexibility and high ionic conductivity. In this study, polybutyl acrylate (PBA) emulsion microspheres are synthesized via emulsion polymerization and introduced as hydrophobic association centers into a poly(vinyl alcohol)/polyacrylamide (PVA/PAAm) double-network hydrogel electrolyte. This electrolyte not only maintains good elasticity but also significantly enhances mechanical strength, demonstrating robust fatigue resistance. By integrating this electrolyte with ammonium molybdate-doped polypyrrole electrodes, a stretchable/compressible supercapacitor is assembled. The resultant supercapacitor exhibits a remarkable specific capacitance retention of 64.5% after 1000 stretch-release cycles under 200% tensile deformation and 68.7% after 1000 compression-release cycles under 80% compression deformation. This work presents a novel approach for designing and constructing advanced hydrogel electrolytes as well as stretchable/compressible supercapacitors.

Enrichment of antioxidant peptides by interfacial modification of oat polypeptides induced by zinc ions.

Oral peptide therapeutics are increasingly favored in the pharmaceutical industry for their ease of use and better patient adherence. However, they face challenges with poor oral bioavailability due to their high molecular weight and surface polarity. Permeation enhancers (PEs) like salcaprozate sodium (SNAC) have shown promise in clinical trials, achieving about 1% bioavailability. One proposed mechanism for enhancing permeation is membrane perturbation or fluidization, though direct experimental proof and quantitative analysis of these effects are still needed. This study employs solid-state NMR (ssNMR) to investigate how SNAC interacts with hydrated DMPC liposomes, measuring enhancements in membrane fluidity across interfacial and transmembrane regions. The methodology involves analyzing phosphate lipid headgroups and acyl chains using static 31P chemical shift anisotropy and 2H quadrupolar coupling measurements alongside 1H and 13C magic angle spinning NMR for motional averaging of 1H-1H and 1H-13C dipolar couplings. Our findings indicate an overall increase in the uniaxial motion of phospholipids with SNAC in a PE concentration-dependent manner. It boosts lipid headgroup dynamics and enhancement plateaus at 25% between 24 and 72 mM concentrations. SNAC effectively enhances the fluidity of the hydrophobic center by 43% at 72 mM PE concentration, more significantly than the interfacial region. It is worth noting that the extent of liposome dissolution and conversion to micelles increases as SNAC concentration rises. Including a model peptide drug, octreotide, introduces a competitive equilibrium in this complex PE-lipid-peptide system, further influencing membrane dynamics for peptide permeation. Interestingly, the membrane enhancement does not show the expected plateau, and a less significant lipid mobility increase is observed in the presence of octreotide, suggesting a less substantial impact compared to peptide-free systems, which is likely due to peptide-PE interactions that consume monomeric SNAC, reducing its interaction with the lipid membrane. This study provides the first quantitative and site-specific ssNMR measurements of membrane mobility influenced by one representative PE as a snapshot of PE lipid interaction in a liposome model, demonstrating how peptide drugs modulate competitive equilibria and PE-induced lipid dynamics.

The five-membered nitrogen-containing heterocyclic moiety imidazole forms part of molecules that have been used to treat various diseases including life-threatening cancer. Moreover, the imidazole moiety is naturally present in various plants, marine, and microorganism-based metabolites and possesses various medicinal benefits. In this review, the pharmacophore-based substitution effect on the imidazole skeleton is primely compiled. A plethora of synthetic approaches have been adopted to develop imidazole hybrids, a number of which have been used as a basic skeleton for synthesizing other fused hybrids. Second, various recent synthetic methods, both in vitro and in vivo activities, are reviewed. Pharmacophoric examination showed that imidazole acts as a ring aromatic, or hydrophobic center depending on the type of substitution. While substitution with benzene ring, it acts only as a hydrogen bond donor and substitution with a hydrophobic ring and an aliphatic long chain on the imidazole ring leads to anticonvulsant and anti-inflammatory activity. The substitution of various electron-sharing features increases the antiulcerogenic property as well as anticancer activity. The results of this review work suggest that fabrication with specific pharmacophoric features aids in the synthesis of selective antagonist for various diseases.

Xanthine oxidase inhibitors: Virtual screening and mechanism of inhibition studies

Cancer is indisputably one of the major threats to mankind, and hence the design of new approaches for the improvement of existing therapeutic strategies is always wanted. Herein, the design of a tumor microenvironment-responsive, DNA-based chemodynamic therapy (CDT) nanoagent with dual Fenton reaction centers for targeted cancer therapy is reported. Self-assembly of DNA amphiphile containing copper complex as the hydrophobic Fenton reaction center results in the formation of CDT-active DNAsome with Cu2+-based Fenton catalytic site as the hydrophobic core and hydrophilic ssDNA protrude on the surface. DNA-based surface addressability of the DNAsome is then used for the integration of second Fenton reaction center, which is a peroxidase-mimicking DNAzyme noncovalently loaded with Hemin and Doxorubicin, via DNA hybridization to give a CDT agent having dual Fenton reaction centers. Targeted internalization of the CDT nanoagent and selective generation of •OH inside HeLa cell are also shown. Excellent therapeutic efficiency is observed for the CDT nanoagent both in vitro and in vivo, and the enhanced efficacy is attributed to the combined and synergetic action of CDT and chemotherapy.

Abstract3D bioprinting is a promising technology which typically uses bioinks to pattern cells and their scaffolds. The selection of cytocompatible inks is critical for the printing success. In laser‐based 3D bioprinting, photoresist molecules are used as bioinks. However, the interaction of photoresists with lipid membranes and their permeation into the cell remains poorly understood. Here, molecular dynamics simulations and in vitro assays address this issue, retrieving partition coefficients, free energies, and permeabilities for twelve commonly used photoresists in model lipid bilayers. Crossing the hydrophobic center of the membrane constitutes the rate limiting step during permeation. In addition, three photoresists feature a preferential localization site at the acyl chain head group interface. Photoresist permeabilities range over ten orders of magnitude, with some molecules being membrane‐permeable on bioprinting timescales. Moreover, permeation correlates well with the oil–water partition coefficients and is severely hampered by the lipid ordering imposed by the lipid saturation. Overall, the mechanism of interaction of photoresists with model lipid bilayers is provided here, helping to classify them according to their residence in the membrane and permeation through it. This is useful information which will help guide the selection of cytocompatible photoresists for 3D bioprinting.

Aqueous Zn-based electrochemical technologies hold promise for large-scale energy storage applications, yet challenges persist in the unsatisfied Zn reversibility arising from an unstable Zn/electrolyte interface. Here, we employ molecular interface engineering using amphiphilic Pluronic triblock copolymers as electrolyte additives to stabilize the Zn anodes. With a balanced hydrophilic–hydrophobic nature, Pluronic F127 adsorbed on the Zn surface constructs a hydrodynamic interphase, where the hydrophobic PPO center shields the Zn surface from water-induced side reactions, while PEO side blocks guide the homogeneous Zn2+ redistribution. Additionally, F127 contributes to the Zn2+ solvation structure to weaken the water activity at the interfacial region. As a result, F127 additive enables cycling durability over 9300 and 3100 h at 1 and 5 mA cm–2, respectively, and considerable cyclability with high-capacity retention across a wide current density range in Zn||VO2 full cells. This study highlights the potential of amphiphilic block copolymers in stabilizing metallic anode interfaces in aqueous electrolytes.

Mixed systems of betaines and anionic surfactants can have a significant synergistic effect and greatly reduce the interfacial tension (IFT), which has attracted an extensive amount of attention. However, this synergistic effect requires an anionic surfactant and betaine molecular size matching, which limits the scope of its application. In this work, we studied three mixed systems of sodium dialkyl sulfosuccinate (AOT) and betaines with different sizes by molecular dynamics simulation and an IFT experiment and explored the interfacial behavior and synergistic mechanism of AOT in single and mixed systems. The hydrophobic tail chain center angle, average rising height of carbon atoms, stretch degree and distance between the terminal carbon atoms of AOT, and tilt angles of betaine were calculated and analyzed in detail. Simulation results showed that the hydrophobic tail chain center angle of AOT in the single system was smaller, and it tended to extend into the oil phase. After being mixed with different betaines, AOT can adjust its size according to the interfacial vacancies of different betaine systems by changing the alkyl chain orientation and forming tighter interfacial films. The IFT experiment showed that betaine/AOT mixed systems achieved a lower IFT value compared with that of the single system, indicating that AOT showed a synergistic effect with betaines with different structures. This study will be importantly instructively significant for the design and research of betaine mixed systems in crude oil exploitation.

As a part of our discovery of plant-based lead molecules, we provide a helpful tool, which helps in identification, designing, optimising, structural modifications, and prediction of curcumin, to discover novel analogs with enhanced bioavailability, pharmacologically safe, and anticancer potential. QSAR (Quantitative structure-activity relationship) and pharmacophore mapping models were developed and further used to design, synthesize, pharmacokinetics, and in vitro</i> evaluation of curcumin analogs for anticancer activity. The QSAR model yielded a high activity-descriptors relationship accuracy (r2) of 84%, a high activity prediction accuracy (rcv2) of 81%, and external set prediction accuracy of 89%. The QSAR study indicates that the five chemical descriptors were significantly correlated with anticancer activity. The important pharmacophore features identified were a hydrogen bond acceptor, a hydrophobic centre, and a negative ionizable centre. The model's predictive ability was evaluated against a set of chemically synthesized curcumin analogs. Among the tested compounds, nine curcumin analogs were found with IC50 values of 0.10 to 1.86 μg/mL. The active analogs were assessed for pharmacokinetics compliance. EGFR was identified as a potential target of synthesized active curcumin analogs through docking studies. Integrating in silico design, QSAR-driven virtual screening, chemical synthesis, and experimental in vitro</i> evaluation may lead to the early discovery of novel and promising anticancer compounds from natural sources. The developed QSAR model and common pharmacophore generation were used as a designing and predictive tool to develop novel curcumin analogs. This study may help optimize the therapeutic relationships of studied compounds for further drug development and their potential safety concerns. This study may guide compound selection and designing novel active chemical scaffolds or new combinatorial libraries of the curcumin series.

Conducting an asymmetric aldol reaction in both micelles and emulsions with high interfacial reactivity and stereoselectivity is achieved by incorporating an organocatalyst in the inherently hydrophobic center of a star-shaped polymer.

It is known that the recommended dietary allowance of selenium (Se) is dangerously close to its tolerable upper intake level. Se is detoxified and excreted in urine as trimethylselenonium ion (TMSe) when the amount ingested exceeds the nutritional level. Recently, we demonstrated that the production of TMSe requires two methyltransferases: thiopurine S-methyltransferase (TPMT) and indolethylamine N-methyltransferase (INMT). In this study, we investigated the substrate recognition mechanisms of INMT and TPMT in the Se-methylation reaction. Examination of the Se-methyltransferase activities of two paralogs of INMT, namely, nicotinamide N-methyltransferase (NNMT) and phenylethanolamine N-methyltransferase (PNMT), revealed that only INMT exhibited Se-methyltransferase activity. Consistently, molecular dynamics simulations demonstrated that dimethylselenide (DMSe) was preferentially associated with the active center of INMT. Using the fragment molecular orbital method, we identified hydrophobic residues involved in the binding of DMSe to the active center of INMT. The INMT-L164R mutation resulted in a deficiency in Se- and N-methyltransferase activities. Similarly, TPMT-R152, which occupies the same position as INMT-L164, played a crucial role in the Se-methyltransferase activity of TPMT. Our findings suggest that TPMT recognizes negatively charged substrates, whereas INMT recognizes electrically neutral substrates in the hydrophobic active center embedded within the protein. These observations explain the sequential requirement of the two methyltransferases in producing TMSe.

Alzheimer's disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results.

Bioinformatics analysis of the sequences of orthologous zinc-containing peptidases of the M15_C subfamily revealed the presence of a conserved tryptophan residue near the active site, which is not involved in the formation of the protein core. Site-directed mutagenesis of this Trp114/109 residue using two representatives of the family, l-alanoyl-d-glutamate peptidases of bacteriophages T5 (calcium-activated EndoT5) and RB49 (EndoRB49, without ion regulation) as examples, and further analysis of the 1H NMR spectra of the mutants showed that a decrease in the volume of the W → F → A residue leads to changes in the hydrophobic core and active center of the protein, and also decreases the affinity for regulatory Ca2+ in the EndoT5 mutants. The inactive T5W114A mutant lacks the ability to bind the substrate. In general, the conserved Trp114/109 residue, due to the spatial restrictions of its side chain, significantly affects the formation of the catalytically active form of the enzyme and is critical for catalysis.

The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple physiological processes and is involved in diverse human diseases such as intrahepatic cholestasis of pregnancy, which is caused by the intracellular accumulation of bile acids and estrogens. Here, we report three cryogenic electron microscopy structures of ABCC3: in the apo-form and in complexed forms bound to either the conjugated sex hormones β-estradiol 17-(β-D-glucuronide) and dehydroepiandrosterone sulfate. For both hormones, the steroid nuclei that superimpose against each other occupy the hydrophobic center of the transport cavity, whereas the two conjugation groups are separated and fixed by the hydrophilic patches in two transmembrane domains. Structural analysis combined with site-directed mutagenesis and ATPase activity assays revealed that ABCC3 possesses an amphiphilic substrate-binding pocket able to hold either conjugated hormone in an asymmetric pattern. These data build on consensus features of the substrate-binding pocket of MRPs and provide a structural platform for the rational design of inhibitors.

Fluorescent probes: 8-anilino-1-naphthalenesulfonate (ANS), eosin Y, and pyrene were used to study the interaction between liposomes and three nitrosyl iron complexes that are promising anti-inflammatory agents and cardioprotectors. It was shown that the studied complexes compete with ANS molecules for the bonding sites in a bilayer of liposomes. The incorporation of the complexes into the lipid bilayer was also studied according to the quenching of eosin Y and pyrene fluorescence. The data suggest that iron nitrosyl complexes interact with the phospholipids headgroups and can penetrate deeper into the hydrophobic center of a lipid bilayer, where they affect the packing of fatty acid chains. The pronounced membranotropic properties of the complexes correlated with their ability to inhibit lipid peroxidation. Complexes with high constants of pyrene bonding are the most effective antioxidants.

As the downstream component of the mitogen-activated protein kinases (MAPK) pathway, the extracellular signal-regulated kinase (ERK) is responsible for phosphorylating a broad range of substrates in cell proliferation, differentiation, and survival. Direct targeting the ERK proteins by the piperidinopyrimidine urea-based inhibitors has been demonstrated to be an effective way to block the MAPK signaling pathway in inhibiting tumor growth. In order to discover better inhibitors, a computer-aided drug design (CADD) approach was employed to reveal the pharmacological characteristics and mechanisms of action. The pharmacophore model was generated on the basis of the compounds with eight features, i.e., four hydrogen bond acceptor atoms, one hydrogen bond donor atom, and three hydrophobic centers. A total of 14 hit compounds were obtained through virtual screening. Two potential inhibitors, namely VS01 and VS02, have been identified by molecular docking and molecular dynamics simulations. Both compounds are capable of attaching to the ERK pocket precisely. The binding free energies of VS01 and VS02 are about 15 kJ/mol and 4 kJ/mol stronger than that of the clinic Ulixertinib because of the characteristic hydrogen bonding, electrostatic, and hydrophilic interactions. The present theoretical investigations shed new light on the rational design of the potential ERK inhibitors to stimulate further experimental tests. Communicated by Ramaswamy H. Sarma