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The current study offers a metal-free, direct, and successful synthesis technique for a new series of quinolinone and benzo[d][1,3]oxazine, along with an assessment of their biological activities. Heteroannulation of anthranilic acid with carbonyl-containing chemicals (aroyl pyruvate, ethyl acetoacetatete, maleic anhydride, and ethyl cyanoacetate) resulted in the desired quinolones and benzo[d][1,3]oxazines. This technique introduces a number of fundamental breakthroughs in organic synthesis, including metal-free catalysts, smart reaction conditions with column purification, and a wide functional scope. Furthermore, the structure of the newly synthesized chemical series was investigated and validated using spectroscopic techniques. The synthesized series were evaluated for antibacterial (against gram-positive and gram-negative bacterial strains) and antifungal activity. The quinolone and benzo[d][1,3]oxazine candidates had remarkable antibacterial action. Furthermore, molecular docking investigations corroborated the biological studies using the Molecular Operating Environment and Petro Osiris Molinspiration (POM) experiments, which confirmed the activity of compounds 8, 15, and 17. Our studies on the cytotoxic activity of various chemicals have demonstrated that these compounds exhibit minimal toxicity. Specifically, when comparing the cytotoxic effects on human lung fibroblast (WI38) cells to those of Doxorubicin, a well-known chemotherapy agent, compounds 8, 15, and 17 showed weak cytotoxic effects on the normal WI38 cells. This indicates that these compounds may possess some level of selectivity and reduced toxicity towards normal cells, suggesting potential for further exploration as antibacterial agents with a safer profile for normal cells. [ABSTRACT FROM AUTHOR]

Summary As global temperatures rise, improving crop yields will require enhancing the thermotolerance of crops. One approach for improving thermotolerance is using bioengineering to increase the thermostability of enzymes catalysing essential biological processes. Photorespiration is an essential recycling process in plants that is integral to photosynthesis and crop growth. The enzymes of photorespiration are targets for enhancing plant thermotolerance as this pathway limits carbon fixation at elevated temperatures. We explored the effects of temperature on the activity of the photorespiratory enzyme glycerate kinase (GLYK) from various organisms and the homologue from the thermophilic alga Cyanidioschyzon merolae was more thermotolerant than those from mesophilic plants, including Arabidopsis thaliana. To understand enzyme features underlying the thermotolerance of C. merolae GLYK (CmGLYK), we performed molecular dynamics simulations using AlphaFold‐predicted structures, which revealed greater movement of loop regions of mesophilic plant GLYKs at higher temperatures compared to CmGLYK. Based on these simulations, hybrid proteins were produced and analysed. These hybrid enzymes contained loop regions from CmGLYK replacing the most mobile corresponding loops of AtGLYK. Two of these hybrid enzymes had enhanced thermostability, with melting temperatures increased by 6 °C. One hybrid with three grafted loops maintained higher activity at elevated temperatures. Whilst this hybrid enzyme exhibited enhanced thermostability and a similar Km for ATP compared to AtGLYK, its Km for glycerate increased threefold. This study demonstrates that molecular dynamics simulation‐guided structure‐based recombination offers a promising strategy for enhancing the thermostability of other plant enzymes with possible application to increasing the thermotolerance of plants under warming climates. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Wilson's disease (WD) results from pathogenic ATP7B gene variations, causing copper accumulation mainly in the liver, brain, and kidneys.In India, despite studies on ATP7B variants, WD often goes undiagnosed, with the prevalence, carrier rate, and mutation spectrum remaining unknown.A multicenter study examined genetic variations in WD among individuals of Indian origin via whole exome sequencing. The study used the InDelible structural variants calling pipeline and conducted molecular dynamic simulations on variants of uncertain significance (VUS) in ATP7B AlphaFold protein structures. Additionally, a high‐throughput gene screening panel for WD was developed.This study examined 128 clinically diagnosed cases of WD, revealing 74 genetically confirmed cases, 22 with ATP7B variants, and 32 without. Twenty‐two novel ATP7B gene variants were identified, including a 322 bp deletion classified as a structural variant. Molecular dynamics simulations highlighted the potential deleterious effects of 11 ATP7B VUS. Gene burden analysis suggested associations with ANO8, LGR4, and CDC7. ATP7B gene hotspots for pathogenic variants were identified. Prevalence and carrier rates were determined as one in 18,678 and one in 67, respectively. A multiplex sequencing panel showed promise for accurate WD diagnosis.This study offers crucial insights into WD's genetic variations and prevalence in India, addressing its underdiagnosis. It highlights the novel genetic variants in the ATP7B gene, the involvement of other genes, a scalable, cost‐effective multiplex sequencing panel for WD diagnosis and management and promising advancements in WD care. [ABSTRACT FROM AUTHOR]

This work was designed to investigate the influence of arsenic dosage, variety on the mechanical properties, hydration, and solidification from the perspective of Portland cement (PC) performance evolution. The results demonstrate that using PC could solidify the arsenic wastes effectively, with arsenic leaching concentrations consistently below 5 mg/L. Arsenic wastes retard cement hydration, leading to a slower rate of hydrates formation, disrupting the calcium silicate hydrate (C–S–H) stacking structure, and thus detrimental to strength development especially at early age. The adverse effect is highly dependent on the arsenic variety. The insoluble calcium arsenate exhibits the least impact, while the arsenates show the largest challenging to immobilization due to the instability of hydrates. Molecular dynamic simulation indicates that arsenic can be chemically immobilized with Ca2+, and be physically adsorbed onto the positively charged C–S–H by forming As‐O···Ca···Si‐O units, accompanied by a significant reduction in adsorption energy by 46.5%. The arsenic solidification behavior provides a basis for the resource utilization of arsenic wastes in cementitious materials. [ABSTRACT FROM AUTHOR]

Smart actuators have shown great potential for a range of industries, including artificial muscles, sensors, and smart devices. However, traditional actuators often suffer from small deformation and complex materials and manufacturing processes. Graphene oxide (GO) has emerged as an ideal candidate for moisture-responsive actuators due to its excellent moisture sensitivity. In this study, we present the development of a moisture-responsive actuator using a simple and straightforward approach based on a monolayer graphene oxide (GO) paper. By utilizing the different affinity of its two sides for water, the graphene oxide actuator demonstrates excellent performance in response to humidity gradients, achieving a large bending amplitude with a curvature of 3 cm−1. Furthermore, the graphene oxide actuator was used as a humidity-sensitive switch to perform on and off switch movements, demonstrating its capability for autonomous detection for real-time humidity monitoring. This work provides a new avenue for the development of moisture-responsive materials and their potential applications in the design of intelligent control systems, actuators, soft robots, artificial muscles, and switches. [Display omitted] • The paper introduces a novel moisture-responsive actuator made of a single layer of graphene oxide paper. • The actuator exploits the different water affinity of its two sides to bend in response to humidity changes. • The actuator can also function as a humidity-sensitive switch, enabling autonomous and real-time humidity detection. • The paper demonstrates the potential of graphene oxide as a material for smart actuators, sensors, and devices. [ABSTRACT FROM AUTHOR]

This work investigates the efficiency of green-synthesized WO3 nanoflakes for the removal of methylene blue dye. The synthesis of WO3 nanoflakes using Hyphaene thebaica fruit extract results in a material with a specific surface area of 13 m2/g and an average pore size of 19.3 nm. A combined theoretical and experimental study exhibits a complete understanding of the MB adsorption mechanism onto WO3 nanoflakes. Adsorption studies revealed a maximum methylene blue adsorption capacity of 78.14 mg/g. The pseudo-second-order model was the best to describe the adsorption kinetics with a correlation coefficient (R2) of 0.99, suggesting chemisorption. The intra-particle diffusion study supported a two-stage process involving surface adsorption and intra-particle diffusion. Molecular dynamic simulations confirmes the electrostatic attraction mechanism between MB and the (002) WO3 surface, with the most favorable adsorption energy calculated as -0.68 eV. The electrokinetic study confirmed that the WO3 nanoflakes have a strongly negative zeta potential of -31.5 mV and a uniform particle size of around 510 nm. The analysis of adsorption isotherms exhibits a complex adsorption mechanism between WO3 and MB, involving both electrostatic attraction and physical adsorption. The WO3 nanoflakes maintained 90% of their adsorption efficiency after five cycles, according to the reusability tests. [ABSTRACT FROM AUTHOR]

This study investigates the effects of natural inhibitors (pomegranate, algae, and tomato extracts) on the corrosion resistance of titanium (grade 2). To deepen understanding the inhibition mechanism, Molecular Dynamic (MD) and Monte Carlo (MC) simulations were employed to analyze adsorption behaviors and identify optimal adsorption sites on titanium oxide (TiO2) surfaces for compounds within the inhibitors. Results indicate non-flat adsorption orientations, with pomegranate peel extract components showing superior inhibition capabilities, attributed to the formation of strong O-H chemical bonds with the TiO2 surface. In the experimental part of the study Electrochemical Impedance Spectroscopy (EIS) and Potentiodynamic Polarization (PDP) were conducted. Two electrolytes were tested: a solution 3.5% NaCl and a solution 0.5 M NaOH. All the tests were performed with 5% of inhibitor and with the reference solution. Also, inhibition efficiency was calculated on the base of PDP tests. The study found that pomegranate extract can act as a good corrosion inhibitor for titanium alloy in aqueous solutions 0.5 M NaOH. This was demonstrated by the increase in the corrosion potential and impedance modulus and decrease in the corrosion current density after the addition of pomegranate extract to the solution. However, in a 3.5% NaCl solution, the efficacy of pomegranate extract was less pronounced, probably due to the high aggressivity of the electrolyte. Tomato and algae extract have instead shown very low inhibition effects in all the tested conditions. [ABSTRACT FROM AUTHOR]

Anti-microbial resistance has emerged as the leading cause of death worldwide with the rise of multidrug-resistant (MDR) bacteria, the need for novel anti-microbials to treat serious illnesses has become a great necessity. Hence, in this study, we aimed to design and synthesize benzothiazole-coupled azetidinone derivatives (GD1-GD12) as novel antibacterial agents. The synthesized compounds were elucidated by nuclear magnetic resonance, infrared and mass spectroscopy. The antibacterial activities of these compounds were tested against antibiotic-susceptible and MDR strains of bacteria. In addition, we performed ADME profiling, molecular docking and molecular dynamic simulations, principle component analysis, dynamic cross-correlation map and free-energy landscape to assess the binding of synthesized compounds with the β -lactamase. Among the synthesized compounds GD6 and GD5 displayed minimum inhibitory concentrations of 12.5 μ g/mL and 50 μ g/mL against MDR strains of E. coli; more effective than standard. The molecular docking of designed molecules was performed against μ -lactamase enzyme and the stability of the complex was vali-dated. The pharmacokinetic profile displayed the compounds to possess druggable properties within the suitable ranges. The in silico approach displayed compound GD6 to be stable with β -lactamase enzyme; indicating the mechanism for these compounds to be via inhibition of β -lactamase. The novel anti-microbial compounds assessed against susceptible and MDR strains of bacteria possess antibacterial potential via the inhibition of β -lactamase. The aforementioned data will be crucial to the development of novel broad-spectrum antibacterial compounds. A novel method was used to design the ligands: Benzothiazole-coupled azetidinone (GD1-12). Their binding affinity and stability to the β -lactamase enzyme inhibitor (3FV7) were assessed using molecular docking and dynamics. Subsequently, compounds (GD1-12) were synthesized, purified, characterized, and tested for antimicrobial activity. Among all the compounds, GD6 exhibited promising antimicrobial activity. [ABSTRACT FROM AUTHOR]

Diabetes remains a critical global public health challenge, posing a growing threat to human health and well-being. White tea is a lightly fermented tea and one of the six traditional tea categories in China. Owing to its rich content of bioactive compounds such as catechins and alkaloids, it has demonstrated potential anti-diabetic properties. However, its precise bioactive components, mechanisms of action, and relevant molecular targets require further investigation. In this study, an integrated approach combining polyphenol-targeted metabolomics, in vitro antioxidant assays, α-glucosidase inhibition tests, network pharmacology analysis, GEO database exploration, molecular docking, and molecular dynamics simulations was employed to identify the potential anti-diabetic compounds, targets, and mechanisms of white tea. The findings revealed that white tea is particularly abundant in 10 bioactive compounds, including epigallocatechin gallate, epicatechin gallate, and catechin, all of which exhibit significant anti-diabetic potential. These compounds were found to exert their effects by interacting with core molecular targets, namely cathepsin V (CTSV) and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and engaging in pathways related to signal transduction, apoptosis, and immune responses. This study establishes a strong theoretical basis for advancing white tea research and underscores new opportunities for applying natural products in diabetes therapy. [ABSTRACT FROM AUTHOR]

VX is a highly toxic organophosphorus nerve agent that the Chemical Weapons Convention classifies as a Schedule 1. In our previous study, we developed a method for detecting organophosphorus compounds using peptide self-assembly. Nevertheless, the self-assembly mechanisms of peptides that bind organophosphorus and the roles of each peptide residue remain elusive, restricting the design and application of peptide materials. Here, we use a multi-scale computational combined with experimental approach to illustrate the self-assembly mechanism of peptide-bound VX and the roles played by residues in different peptide sequences. We calculated that the self-assembly of peptides was accelerated after adding VX, and the final size of assembled nanofibers was larger than the original one, aligning with experimental findings. The atomic scale details offered by our approach enabled us to clarify the connection between the peptide sequences and nanostructures formation, as well as the contribution of various residues in binding VX and assembly process. Our investigation revealed a tight correlation between the number of Tyrosine residues and morphology of the assembly. These results indicate a self-assembly mechanism of peptide and VX, which can be used to design functional peptides for binding and hydrolyzing other organophosphorus nerve agents for detoxification and biomedical applications. [ABSTRACT FROM AUTHOR]

The NEK6 (NIMA-related kinase 6) serine/threonine kinase is a pivotal player in a multitude of cellular processes, including the regulation of the cell cycle and the response to DNA damage. Its significance extends to disease pathogenesis, as changes in NEK6 activity have been linked to the development of cancer. Non-synonymous single nucleotide polymorphisms (nsSNPs) in NEK6 have been linked to cancer as they alter the protein's native structure and function. The association between NEK6 activity and cancer development has prompted researchers to explore the effects of genetic variations within the NEK6 gene. Therefore, we utilized advanced computational tools to analyze 155 high-confidence nsSNPs in the NEK6 gene. From this analysis, 21 nsSNPs were identified as potentially harmful, raising concerns about their impact on NEK6 activity and cancer risk. These 21 mutations were then examined for structural alterations, and eight of nsSNPs (I51M, V76A, I134N, Y152D, R171Q, V186G, L237R, and C285S) were found to destabilize the protein. Among the destabilizing mutations screened, a specific mutation, R171Q, stood out due to its conserved nature. To understand its impact on the protein and conformation, all-atom molecular dynamics simulations (MDS) for 100 ns were performed for both Wildtype NEK6 (WT-NEK6) and R171Q. The simulations revealed that the R171Q variant was unstable and led to significant conformational changes in NEK6. This study provides valuable insights into NEK6 dysfunction caused by single amino acid alterations, offering a novel understanding of the molecular mechanisms underlying NEK6-related cancer progression. [ABSTRACT FROM AUTHOR]

This study delved into the exploration of bioactive constituent profiling of Floscopa scandens Lour. by using HRLC‐MS. The plant is well‐known as a folklore herb. It is extensively utilized in traditional medicine to address various ailments such as fractures, sore eyes, fevers, abscesses, pyoderma, and acute nephritis. This study aimed to explore the phytochemical composition of F. scandens and assess the anti‐inflammatory activity of the ecdysterone marker compound by molecular docking studies followed by MD simulations. Extracts were prepared using hexane, chloroform, and methanol solvents. Chromatographic techniques were applied to isolate compounds from the methanol extract, which underwent phytochemical screening via HR‐LCMS. Functional groups were assessed using NMR and Fourier transform infrared (FTIR), confirming the presence of bioactive compounds. HR‐LCMS analysis identified 21 phytoconstituents in the methanolic fraction, with ecdysterone being a prominent component characterized through spectroscopic techniques. Our findings confirm known molecules while unveiling new bioactive constituents, particularly highlighting the potential of ecdysterone as a novel chemical entity. Molecular docking and molecular dynamic simulation analysis further show the anti‐inflammatory properties of ecdysterone with various enzymes in the body. [ABSTRACT FROM AUTHOR]

Crimean–Congo hemorrhagic fever virus (CCHFV) belongs to Nairoviridae family and has tripartite RNA genome. It is endemic in various countries of Asia, Africa, and Europe and is primarily transmitted by Hyalomma ticks but nosocomial transmission also been reported. Vaccines for CCHF are in early phase of clinical trial; therefore, this work is centered on identification of potential immunogenic peptide as vaccine candidates with application of different immunoinformatics approaches. Eleven conserved (>90%) peptides of CCHFV nucleoprotein were selected for CD8+ T‐cell (NetMHCpan 4.1b and NetCTLpan 1.1 server) and CD4+ T‐cell (NetMHCIIpan‐4.0 server and Tepitool) epitope prediction. Three peptides containing multiple CD8+ and CD4+ T‐cell and B‐cell epitopes were identified on basis of consensus prediction approach. Peptides displayed good antigenicity score of 0.45–0.68 and predicted to bind with diverse human leukocyte antigen (HLA) alleles. Molecular docking was performed with epitopes to HLA and HLA‐epitopes complex to T‐cell receptor (TCR). In most of the cases, docked complex of HLA‐epitope and HLA‐epitopes‐TCR have the binding energy close to respective natural bound peptide complex with HLA and TCR. Molecular dynamic simulation also revealed that HLA‐peptide complexes have minimum fluctuation and deviation than HLA‐peptide‐TCR docked over 50 ns simulation run. Considering these findings, identified peptides can serve as potential vaccine candidates for CCHFV disease. [ABSTRACT FROM AUTHOR]

AbstractCancer is a significant worldwide health concern that requires effective therapies. Addressing this critical issue necessitates innovative treatment strategies concentrating on the fundamental causes of cancer progression. The PARP15 protein is essential in cancer progression by facilitating DNA repair pathways, making it a promising target for anti-cancer therapies. This investigation relies on computational strategies, including virtual screening and molecular dynamics simulations, to identify potential inhibitors of PARP15 target protein. Three potential compounds (26646684, 104224077, and 17505556) with notable binding affinities and interaction patterns were selected for further investigation. Compound 17505556 shows significant interactions, suggesting more stable conformation throughout the simulation against the target protein. Compound 17505556 exhibited the highest binding free energy (-34.07 kcal/mol), significantly outperforming the reference inhibitor I4X (-26.70 kcal/mol). This strong binding affinity suggests that 17505556 forms stable and sustained interactions with PARP15, making it the most promising inhibitor among those studied. Other compounds, 26646684 (-28.92 kcal/mol) and 104224077 (-26.83 kcal/mol), also demonstrated favorable binding energies, indicating their potential as viable inhibitors. The overall result of the investigation suggests the compound 17505556 as a possible drug candidate for the inhibition of DNA repair protein, offering novel avenues for developing an anti-cancer drug candidate. [ABSTRACT FROM AUTHOR]

Rare‐earth (RE)‐doped laser glasses meet urgent needs in national security and scientific fields, and their optimization has garnered extensive attention. However, the design of these laser glasses often relies excessively on trial‐and‐error experimentation, leading to significant costs and a lack of scientific guidance. Herein, we propose an integrated method that combines structural descriptors determined from molecular dynamics simulations, a self‐constructed luminescent database, and a machine learning algorithm to establish the composition–structure–luminescent property (CSLP) relationship. Using an Nd3+‐doped commercial silicate laser glass system as an example, the effectiveness of this approach has been demonstrated. The developed CSLP model enables highly accurate predictions of spectral properties, achieving a determination coefficient (R2) greater than 0.94, based on eight structural descriptors. The importance of different structural descriptors on spectral characteristics is ranked and thoroughly discussed, revealing an intrinsic relationship between the first and second coordination shells around RE ions and luminescent behaviors. Furthermore, the generic structural descriptors identified in the CSLP model can be extrapolated to other systems involving different network formers (e.g., silicate and phosphate) and modifier cations (e.g., Li, Na, K, Ba, and Ca). This capability facilitates the design of laser glasses tailored to specific targets, such as large emission cross‐sections, extended lifetimes, or reduced quenching effects. [ABSTRACT FROM AUTHOR]

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn's disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies. [ABSTRACT FROM AUTHOR]

Rare diseases and conditions have thus far received relatively less attention in the field of precision/personalized medicine than common chronic diseases. There is a dire need for orphan drug discovery and therapeutics in ways that are informed by the precision/personalized medicine scholarship. Moreover, people with rare conditions, when considered collectively across diseases worldwide, impact many communities. In this overarching context, Activin A Receptor Type 1 (ACVR1) is a transmembrane kinase from the transforming growth factor-β superfamily and plays a critical role in modulating the bone morphogenetic protein signaling. Missense variants of the ACVR1 gene result in modifications in structure and function and, by extension, abnormalities and have been predominantly linked with two rare conditions: fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. We report here an extensive bioinformatic analyses assessing the pool of 50,951 variants and forecast seven highly destabilizing mutations (R206H, G356D, R258S, G328W, G328E, R375P, and R202I) that can significantly alter the structure and function of the native protein. Protein–protein interaction and ConSurf analyses revealed the crucial interactions and localization of highly deleterious mutations in highly conserved domains that may impact the binding and functioning of the protein. cBioPortal, CanSAR Black, and existing literature affirmed the association of these destabilizing mutations with posterior fossa ependymoma, uterine corpus carcinoma, and pediatric brain cancer. The current findings suggest these deleterious nonsynonymous single nucleotide polymorphisms as potential candidates for future functional annotations and validations associated with rare conditions, further aiding the development of precision medicine in rare diseases. [ABSTRACT FROM AUTHOR]

Outbreaks of human Nipah virus (NiV) cases have recently been reported in several countries. With a mortality rate of around 80% and no known therapy, there is an urgent need to test existing antivirals repurposed for it. Due to its central role in virus replication, the RNA-dependent RNA polymerase (RdRp) of NiV-L protein is a potential target for such antiviral therapies. In this study, Favipiravir, Remdesivir, Ribavirin, and their metabolites, including monophosphate (MP), diphosphate (DP), and triphosphate (TP), were virtually screened against RdRp. Using molecular dynamics (MD) simulations, lead hits from the docking study were examined for conformational changes. Additional analyses, including MM-PBSA, residual decomposition energy, and principal component analysis, were performed on the MD trajectory. Remdesivir-TP, Favipiravir-TP, and Ribavirin-TP exhibited the lowest binding energies of –7.8, −7.4, and −6.9 kcal/mol, respectively, and displayed an affinity for pocket 1, forming interactions with active site residues Asp726 and Asn727. During the 100 ns MD simulation, Remdesivir-TP demonstrated a more stable binding mode compared to Favipiravir-TP and Ribavirin-TP. The relative binding energies were −94.709 kJ/mol, −68.882 kJ/mol, and −46.98 kJ/mol for Remdesivir-TP, Favipiravir-TP, and Ribavirin-TP, respectively. This research anticipates Remdesivir-TP to be a potential candidate for an antiviral drug against NiV infection. [ABSTRACT FROM AUTHOR]

Glycylglycine (Gly–Gly) is a crucial biochemical reagent widely used in cosmetics, food additives, and medicine. Using the equilibrium method, the solubility data of Gly–Gly in four binary solvents (ethanol/isopropanol/ethanediol/acetone + water) were investigated at temperatures over a range of 288.15–328.15 K under 101.3 kPa, as well as in the binary solvent of acetic acid + water from 293.15 to 333.15 K. The solubility data were correlated by Apelblat-Jouyban Acree, Van't Hoff-Jouyban Acree, and CNIBS/Redlich-Kister models. Additionally, the radial distribution function was obtained through molecular dynamic simulation. It presented the unusual dissolution behavior of Gly–Gly in acetic acid and water mixture. The apparent thermodynamic properties, including standard enthalpy, Gibbs free energy, and entropy change of dissolution, were obtained accordingly. This article could help the industrial crystallization of Gly–Gly. [ABSTRACT FROM AUTHOR]

Developing highly active alloy catalysts that surpass the performance of platinum group metals in the oxygen reduction reaction (ORR) is critical in electrocatalysis. Gold-based single-atom alloy (AuSAA) clusters are gaining recognition as promising alternatives due to their potential for high activity. However, enhancing its activity of AuSAA clusters remains challenging due to limited insights into its actual active site in alkaline environments. Herein, we studied a variety of Au54M1 SAA cluster catalysts and revealed the operando formed MOx(OH)y complex acts as the crucial active site for catalyzing the ORR under the basic solution condition. The observed volcano plot indicates that Au54Co1, Au54M1, and Au54Ru1 clusters can be the optimal Au54M1 SAA cluster catalysts for the ORR. Our findings offer new insights into the actual active sites of AuSAA cluster catalysts, which will inform rational catalyst design in experimental settings. [ABSTRACT FROM AUTHOR]

Aflatoxins are toxic chemicals produced by Aspergillus fungi. Reports exist on the relationship of aflatoxin exposure via contaminated food and feed to hepatotoxicity and liver cancer. Aflatoxin B1 (AFB1) and Aflatoxin G1 (AFG1) are two dangerous types of aflatoxins for human health. Bovine α-lactalbumin (ALA) is the second major whey protein in milk which bear diverse biological functions. In this study, the interaction of AFB1 and AFG1 with the ALA protein was studied using fluorescence spectroscopy, molecular docking and molecular dynamic (MD) simulation. The spectroscopy experiments showed that the interaction with AFB1 and AFG1significantly quenched the intrinsic fluorescence emission of ALA via a static quenching mechanism. The free energy of binding and binding constant (Ka) obtained from the intrinsic fluorescence results were -5.32 kcal per mol and 0.80 × 104 L mol-1 for AFB1 and -5.64 kcal per mol and 1.35 × 104 l mol-1 for AFG1, respectively. Molecular docking studies were conducted before and after the MD simulation to estimate the binding sites, Ka s and binding mode. Results from the molecular docking showed that AFB1 and AFG1 bound to ALA via hydrophobic interaction and hydrogen bond. After MD simulation, the precision of the Ka obtained from the docking results was improved and it was more similar to the experimental results of fluorescence spectroscopy. Other simulation results were aligned well with the molecular docking and fluorescence spectroscopy results. Accordingly, AFB1and AFG1 could form complex with ALA, however, AFG1 showed higher affinity for binding to ALA and more compact complex structure. [ABSTRACT FROM AUTHOR]

Mycobacterial membrane protein Large 3 (MmpL3) of Mycobacterium tuberculosis (Mtb) is crucial for the translocation of trehalose monomycolate (TMM) across the inner bacterial cell membrane, making it a promising target for anti‐tuberculosis (TB) drug development. While several structural, microbiological, and in vitro studies have provided significant insights, the precise mechanisms underlying TMM transport by MmpL3 and its inhibition remain incompletely understood at the atomic level. In this study, molecular dynamic (MD) simulations for the apo form and seven inhibitor‐bound forms of Mtb MmpL3 were carried out to obtain a thorough comprehension of the protein's dynamics and function. MD simulations revealed that the seven inhibitors in this work stably bind to the central channel of the transmembrane domain and primarily forming hydrogen bonds with ASP251, ASP640, or both residues. Through dynamical cross‐correlation matrix and principal component analysis analyses, several types of coupled motions between different domains were observed in the apo state, and distinct conformational states were identified using Markov state model analysis. These coupled motions and varied conformational states likely contribute to the transport of TMM. However, simulations of inhibitor‐bound MmpL3 showed an enlargement of the proton channel, potentially disrupting coupled motions. This indicates that inhibitors may impair MmpL3's transport function by directly blocking the proton channel, thereby hindering coordinated domain movements and indirectly affecting TMM translocation. [ABSTRACT FROM AUTHOR]

Background and objectives: The cyclic adenosine monophosphate Receptor Protein of Mycobacterium tuberculosis (CRPMt) (Rv3676), is a global transcriptional regulator and plays a pivotal role in the survival and infection of Mycobacterium. This signaling protein (CRPMt) shares several common structural and functional features with the CRP from Escherichia coli. Structurally, CRPMt is a homodimer that undergoes allosteric changes upon cyclic AMP binding. This binding also triggers the activation of several genes responsible for various physiological processes in this bacterium. Despite the importance of CRP for mycobacterial survival, limited information is available regarding the stability and unfolding properties of the protein. The main objective of this study is to study stability, unfolding and dynamics of CRPMt in terms of its structure. Methods: In this study, we monitored the stability and unfolding of CRPMt using various biophysical and computational techniques. Results: We experimentally studied protein unfolding in the presence of chemical denaturants [urea and guanidine hydrochloride (GdnHCl)]. The results from these chemical-induced unfolding studies suggest that CRPMt follows a two-state transition and that chemical-induced protein denaturation is reversible. According to circular dichroism and activity data, CRPMt structure and function were restored upon refolding. We also studied the stability and unfolding of the CRPMt protein against temperature variations and protease action (trypsin). Limited proteolysis experiments provide insights into the minimum domain structure requirement for CRPMt activity. Interestingly, temperature-induced CRPMt unfolding was completely different compared to chemical-induced unfolding. The thermal unfolding of CRPMt was found to be irreversible, leading to the formation of insoluble aggregates at elevated temperatures. To understand why the thermal unfolding of the protein differed from chemically induced unfolding, we carried out a detailed molecular dynamics simulation analysis of the protein at three different temperatures. The results from these molecular dynamics simulations mechanistically validate the significant differences between chemical and temperature-induced CRPMt unfolding. Conclusion: Our study provides detailed insights into the stability and folding/unfolding properties of CRPMt, which could be useful in developing new anti-mycobacterial medicines. [ABSTRACT FROM AUTHOR]

Dental caries, a persistent oral health challenge primarily linked to Streptococcus mutans, extends its implications beyond dental decay, affecting over 4 billion individuals globally. Despite its historical association with childhood, dental caries often persists into adulthood with prevalence rates ranging from 60 to 90% in children and 26 to 85% in adults. Currently, there is a dearth of multiepitope vaccines (MEVs) specifically designed to combat S. mutans. To address this gap, we employed an immunoinformatics approach for MEV design, identifying five promising vaccine candidates (PBP2X, PBP2b, MurG, ATP-F, and AGPAT) based on antigenicity and conservation using several tools including CELLO v.2.5, Vaxign, v2.0, ANTIGENpro, and AllerTop v2.0 tools. Subsequent identification of linear B-cell and T-cell epitopes by SVMTrip and NetCTL/NetMHC II tools, respectively, guided the construction of a MEV comprising 10 Cytotoxic T Lymphocyte (CTL) epitopes, 5 Helper T Lymphocyte (HTL) epitopes, and 5 linear B-cell epitopes, interconnected by suitable linkers. The resultant MEV demonstrated high antigenicity, solubility, and structural stability. In silico immune simulations showcased the MEV's potential to elicit robust humoral and cell-mediated immune responses. Molecular docking studies revealed strong interactions between the MEV construct and Toll-Like Receptors (TLRs) and Major Histocompatibility Complex (MHC) molecules. Remarkably, the MEV–TLR-4 complexes exhibited a low energy score, high binding affinity, and a low dissociation constant. The Molecular Dynamic (MD) simulation analysis suggested that MEV–TLR-4 complexes had the highest stability and minimal conformational changes indicating equilibrium within 40 nanosecond time frames. Comprehensive computational analyses strongly support the potential of the proposed MEV to combat dental caries and associated infections. The study's computational assays yielded promising results, but further validation through in vitro and in vivo experiments is needed to assess its efficacy and safety. [ABSTRACT FROM AUTHOR]

Background and Objectives: Middle East Respiratory Syndrome (MERS) is a viral respiratory illness caused by a coronavirus called Middle East respiratory syndrome. In the current study, immunoinformatics studies were applied to design an epitope-based vaccine construct against Middle East Respiratory Syndrome. Materials and Methods: In this study, epitopes base vaccine construct was designed against MERS using immunoinformatics approach. Results: In this approach, the targeted proteins were screened, and probable antigenic, non-allergenic, and good water-soluble epitopes were selected for vaccine construction. In vaccine construction, the selected epitopes were joined by GPGPG linkers, and a linear multi-epitope vaccine was constructed. The vaccine construct underwent a physiochemical property analysis. The 3D structure of the vaccine construct was predicted and subjected to refinement. After the refinement, the 3D model was subjected to a molecular docking analysis, TLRs (TLR-3 and TLR-9) were selected as receptors for vaccine construct, and the molecular docking analysis study determined that the vaccine construct has binding ability with the targeted receptor. Conclusions: The docking analysis also unveils that the vaccine construct can properly activate immune system against the target virus however experimental validation is needed to confirm the in silico findings further. [ABSTRACT FROM AUTHOR]

Bioconjugation is one of the most promising strategies to improve drug delivery, especially in cancer therapy. Biomolecules such as bile acids (BAs) have been intensively explored as carriers, due to their peculiar physicochemical properties and biocompatibility. BAs trafficking is regulated by intracellular lipid-binding proteins and their transport in the liver can be studied using chicken liver Bile Acid-Binding Proteins (cL-BABPs) as a reference model. Therefore, we conceived the idea of developing a BA-conjugate with Mirin, an exonuclease inhibitor of Mre11 endowed with different anticancer activities, to direct its transport to the liver. Following computational analysis of various BAs in complex with cL-BABP, we identified cholic acid (CA) as the most promising candidate as carrier, leading to the synthesis of a novel bioconjugate named CA-M11. As predicted by computational data and confirmed by X-ray crystallographic studies, CA-M11 was able to accommodate into the binding pocket of BABP. Hence, it can enter BAs trafficking in the hepatic compartment and here release Mirin. The effect of CA-M11, evaluated in combination with varying concentrations of Doxorubicin on HepG2 cell line, demonstrated a significant increase in cell mortality compared to the use of the cytotoxic drug or Mirin alone, thus highlighting chemo-sensitizing properties. The promising results regarding plasma stability for CA-M11 validate its potential as a valuable agent or adjuvant for hepatic cancer therapy. [ABSTRACT FROM AUTHOR]

Flacourtia jangomas is a plant used for centuries in Brazil, China, India, and the Malaya Peninsula to treat conditions such as diabetes, asthma, anaemia, and diarrhoea. Despite its therapeutic and economic benefits, the plant has not been popular among farmers due to its limited yield and lack of knowledge about its potential. Targeting PPARγ agonists is a promising approach for discovering and developing effective drugs to treat type 2 diabetes. Due to the activation of the PPARγ through PPARγ agonists, target genes implicated in inflammation, adipogenesis, lipid metabolism, and glucose metabolism are transcriptionally regulated. This study analysed the curated datasets of F. jangomas to identify the binding conformations of the phytoconstituents with different T2DM targets through molecular docking, molecular dynamics, and ADMET prediction approach. To determine the most favourable binding conformations of phytoconstituents that bind with the PPARγ receptors, density functional theory and principal component analysis were performed. The study reveals that the phytoconstituents of F. jangomas can act as PPARγ agonists and could be used to design and optimise the potential antidiabetic agents inspired by natural products. These findings provide a promising approach towards developing effective antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Background: Although the Chufeng Qingpi Decoction (CQD) has demonstrated clinical effectiveness in the treatment of schistosomiasis, the precise active components and the underlying mechanisms of its therapeutic action remain elusive. To achieve a profound comprehension, we incorporate network pharmacology, bioinformatics analysis, molecular docking, and molecular dynamics simulations as investigative methodologies within our research framework. Method: Utilizing TCMSP and UniProt, we identified formula components and targets. Cytoscape 3.10.0 was used to construct an herb-target interaction network. Genecards, DisGeNET, and OMIM databases were examined for disease-related objectives. A Venn diagram identified the intersection of compound and disease targets. Using Draw Venn, overlapping targets populated STRING for PPI network. CytoNCA identified schistosomiasis treatment targets. GO & KEGG enrichment analysis followed High-scoring genes in PPI were analyzed by LASSO, RF, SVM-RFE. Molecular docking & simulations investigated target-compound interactions. Result: The component's target network encompassed 379 nodes, 1629 edges, highlighting compounds such as wogonin, kaempferol, luteolin, and quercetin. Amongst the proteins within the PPI network, PTGS2, TNF, TGFB1, BCL2, TP53, IL10, JUN, MMP2, IL1B, and MYC stood out as the most prevalent entities. GO and KEGG revealed that mainly involved the responses to UV, positive regulation of cell migration and motility. The signal pathways encompassed Pathways in cancer, Lipid and atherosclerosis, Fluid shear stress and atherosclerosis, as well as the AGE-RAGE. Bioinformatics analysis indicated TP53 was the core gene. Ultimately, the molecular docking revealed that wogonin, kaempferol, luteolin, and quercetin each exhibited significant affinity in their respective interactions with TP53. Notably, kaempferol exhibited the lowest binding energy, indicating a highly stable interaction with TP53. Lastly, we validated the stability of the binding interaction between the four small molecules and the TP53 through molecular dynamics simulations. The molecular dynamics simulation further validated the strongest binding between TP53 and kaempferol. In essence, our research groundbreaking in its nature elucidates for the first time the underlying molecular mechanism of CQD in the therapeutic management of schistosomiasis, thereby providing valuable insights and guidance for the treatment of this disease. Conclusion: This study uncovered the efficacious components and underlying molecular mechanisms of the Chufeng Qingpi Decoction in the management of schistosomiasis, thereby offering valuable insights for future fundamental research endeavors. [ABSTRACT FROM AUTHOR]

With the aim of finding the plant-derived allosteric inhibitors of caspase-3/-7, we conducted computational investigations of bioactive compounds present in various berry fruits. In a molecular docking study, perulactone demonstrated excellent binding affinity scores of −12.1 kcal/mol and −9.1 kcal/mol for caspase 7 and 3, respectively, whereas FDA-approved allosteric inhibitors (DICA and FICA) were found to show lower docking scores (−5.6 and −6.1 kcal/mol) against caspase 7 while (−5.0 and −5.1 kcal/mol) for caspase 3, respectively. MD simulations were used to validate the binding stability of perulactone in the active sites of caspase-7/-3, and the results showed outstanding stability with lower ligand RMSDs of 1.270–3.088 Å and 2.426–9.850 Å against the targeted receptor. Furthermore, we performed MMGBSA free binding energy, where the perulactone values of ΔGBind were determined to be −63.98 kcal/mol and −66.32 kcal/mol for both receptors (3IBF and 1NME), which are significantly better than the −45.16 kcal/mol and −39.51 kcal/mol for DICA as well as −26.37 kcal/mol and −15.50 kcal/mol for FICA, respectively. The drug resemblance of perulactone was effectively evaluated by ADMET. Thus, our findings indicated that perulactone could be an orally administered therapeutic candidate for regulating apoptosis in a variety of disorders. However, there may be an urgent need to study using in vitro and in vivo experiments. [ABSTRACT FROM AUTHOR]

Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-β-D-glucopyranoside, and limonin 17-O-β-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-β-D-glucopyranoside and limonin 17-O-β-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-β-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-β-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

The extraction of the structural features of materials is fundamental for investigating novel properties in fields such as electronic information and biochemistry. However, existing experimental methods have limitations in analyzing material structures with sufficient depth. Therefore, rapid and accurate extraction and analysis of structural features from atomic coordinates obtained through simulation calculations are crucial for advancing the exploration of new material properties. Herein, we propose an approach for extracting the structural features of materials by combining the holographic matrix method with Bayesian optimization and tensor flow operations. The proposed algorithm efficiently classifies and statistically analyzes cluster structures within materials. Experimental validation conducted on a system comprising 8000 atoms demonstrated a correct recognition rate exceeding 99.213%. Moreover, the algorithm achieved an average recognition time of approximately 1. 8 1 ± 0. 0 3 s. The proposed analytical framework exhibits scalability and robustness, establishing an algorithmic foundation for future advancements in big data analytics for complex materials. [ABSTRACT FROM AUTHOR]

Functionally bivalent non-covalent Fab dimers (Bi-Fabs) specific for the TCR/CD3 complex promote CD3 signaling on T cells. While comparing functional responses to stimulation with Bi-Fab, F(ab')2 or mAb specific for the same CD3 epitope, we observed fratricide requiring anti-CD3 bridging of adjacent T cells. Surprisingly, anti-CD3 Bi-Fab ranked first in fratricide potency, followed by anti-CD3 F(ab')2 and anti-CD3 mAb. Low resolution structural studies revealed anti-CD3 Bi-Fabs and F(ab')2 adopt similar global shapes with CD3-binding sites oriented outward. However, under molecular dynamic simulations, anti-CD3 Bi-Fabs crosslinked CD3 more rigidly than F(ab')2. Furthermore, molecular modelling of Bi-Fab and F(ab')2 binding to CD3 predicted crosslinking of T cell antigen receptors located in opposing plasma membrane domains, a feature fitting with T cell fratricide observed. Thus, increasing rigidity of Fab-CD3 crosslinking between opposing effector-target pairs may result in stronger T cell effector function. These findings could guide improving clinical performance of bi-specific anti-CD3 drugs. [ABSTRACT FROM AUTHOR]

This manuscript presents the results from the synthesis and characterization of a slag analogue with a nominal composition of 17 wt% LiMnO2 and 83 wt% Ca2SiO4 encountering fairly high cooling rates in order to study the evolution of Mn-species. The Mn species was also simulated from 1223 K to 1773 K using a thermodynamic model, assuming a homogeneous melt. The micro-composition including the Mn species of the solidified slag was determined experimentally, and was used as basis for molecular dynamics (MD) simulation. The MD simulation provides information on structure and viscosity at high temperatures, which are otherwise difficult to access. These parameters significantly influence oxidation state of redox-active elements and the solidified product. The micro-composition analyzed by electron probe micro analysis (EPMA) and synchrotron-based micro-X-ray fluorescence (micro-XRF) showed that Mn-rich and Ca-Si-rich phases are separated. While the Mn-O phases did not contain noticeable Ca, the Ca2SiO4 phase had incorporated 0.6 wt% of Mn. The slag solidified into round-shaped and droplet-shaped grains of a Li-Mn-oxide, some Mn3O4 and Ca2SiO4. The powder X-ray diffraction (PXRD) confirmed the formation of larnite; the identity of the Li-Mn-oxide, however, remained inconclusive. The Mn oxidation state (OS) was identified using synchrotron-based micro-X-ray absorption near edge spectroscopy (micro-XANES). The Mn-O grains matched well with Li-Mn-oxides and a Mn OS: +3, e.g., LiMn3+O2. Small areas matching hausmannite (Mn2+Mn23+O4) were also identified. The OS of Mn in the silicate phase could not be identified. For comparison, a slowly cooled slag analogue with similar composition, but higher Si content, was also subjected to micro-XANES. The slowly cooled slag formed long Mn-rich needles in a matrix of large calcium silicate crystals. The Mn-rich crystals matched well with the XANES spectrum of a Mn3+ Li-oxide like LiMn3+O2. At the rim of the needles, the Mn-spectra matched well the hausmannite (Mn2+Mn23+O4) reference. In the silicate phases, Mn had an OS: +2, unambiguously. The melt structure at different temperatures of two compositions, i.e., LiMn3+O2 and Ca2SiO4, was simulated using molecular dynamics (MD). They serve as model compositions, assuming a heterogeneous melt. The results show significant different degrees of polymerization and viscosity. Information from MD simulations can support the identification of potentially different oxygen permeability and with that prediction of oxidation states. The bulk composition was identified by inductively coupled plasma optical emission spectrometry (ICP-OES), bulk structure by PXRD and bulk species by lab-XANES. The synchrotron micro analysis including micro-XRD were performed at the microfocus beamline I18 at the Diamond Light Source. Pure reference compounds were prepared and characterized with the same multi-modal approach. [ABSTRACT FROM AUTHOR]

A novel tick-borne orthonairovirus called the Yezo virus (YEZV), primarily transmitted by the Ixodes persulcatus tick, has been recently discovered and poses significant threats to human health. The YEZV is considered endemic in Japan and China. Clinical symptoms associated with this virus include thrombocytopenia, fatigue, headache, leukopenia, fever, depression, and neurological complications ranging from mild febrile illness to severe outcomes like meningitis and encephalitis. At present, there is no treatment or vaccine readily accessible for this pathogenic virus. Therefore, this research employed an immunoinformatics approach to pinpoint potential vaccine targets within the YEZV through an extensive examination of its structural proteins. Three structural proteins were chosen using specific criteria to pinpoint T-cell and B-cell epitopes, which were subsequently validated through interferon-gamma induction. Six overlapping epitopes for cytotoxic T-lymphocytes (CTL), helper T-lymphocytes (HTL), and linear B-lymphocytes (LBL) were selected to construct a multi-epitope vaccine, achieving a 92.29% coverage of the global population. These epitopes were then fused with the 50S ribosomal protein L7/L12 adjuvant to improve protection against international strains. The three-dimensional structure of the designed vaccine construct underwent an extensive evaluation through structural analysis. Following molecular docking studies, the YEZV vaccine construct emerged as a candidate for further investigation, showing the lowest binding energy (−78.7 kcal/mol) along with favorable physiochemical and immunological properties. Immune simulation and molecular dynamics studies demonstrated its stability and potential to induce a strong immune response within the host cells. This comprehensive analysis indicates that the designed vaccine construct could offer protection against the YEZV. It is crucial to conduct additional in vitro and in vivo experiments to verify its safety and effectiveness. [ABSTRACT FROM AUTHOR]

In view of the current problems of slow crystallization rate, varying grain sizes, complex process conditions, and low safety in the preparation of CL−20/TNT cocrystal explosives in the laboratory, an opposite spray crystallization method is provided to quickly prepare ultrafine explosive cocrystal particles. CL−20/TNT cocrystal explosive was prepared using this method, and the obtained cocrystal samples were characterized by electron microscopy morphology, differential thermal analysis, infrared spectroscopy, and X-ray diffraction analysis. The effects of spray temperature, feed ratio, and preparation method on the formation of explosive cocrystal were studied, and the process conditions of the pneumatic atomization spray crystallization method were optimized. The crystal plane binding energy and molecular interaction forces between CL−20 and TNT were obtained through molecular dynamic simulation, and the optimal binding crystal plane and cocrystal mechanism were analyzed. The theoretical calculation temperature of the binding energy was preliminarily explored in relation to the preparation process temperature of cocrystal explosives. The mechanical sensitivity of ultrafine CL−20/TNT cocrystal samples was tested. The results showed that choosing acetone as the cosolvent, a spraying temperature of 30 °C, and a feeding ratio of 1:1 was beneficial for the formation and growth of cocrystal. The prepared CL−20/TNT cocrystal has a particle size of approximately 10 μm. The grain size is small, and the crystallization rate is fast. The impact and friction sensitivity of ultrafine CL−20/TNT cocrystal samples were significantly reduced. The experimental process conditions are simple and easy to control, and the safety of the preparation process is high, providing certain technical support for the preparation of high-quality cocrystal explosives. [ABSTRACT FROM AUTHOR]

Diabetes, a chronic metabolic disease, has become a severe health problem worldwide. According to the latest data from the International Diabetes Federation (IDF), there were 537 million diabetic mellitus (DM) patients worldwide in 2021, expected to increase to 783 million by 2045. Over 90% of people with diabetes have type 2 diabetes, which is driven by socio-economic, demographic, environmental, and genetic factors. Diabetes is still a major global health issue, with prevalence rates rising all across the world. This not only imposes a significant burden on healthcare systems but also impacts the quality of life of affected individuals and their families. Therefore, there is a continuous high demand worldwide to develop novel, more effective, and easily affordable medications against diabetes. This paper illustrates the in-vitro antidiabetic activity and probable binding mechanism prediction of phytoconstituents of Allamanda cathartica against type 2 diabetes molecular targets. Through the application of bioactivity score prediction, molecular docking, and ADMET prediction approach, the potential and selective phytoconstituents with the highest binding affinity and lower toxicity were gained from the curated datasets. Further molecular dynamics simulations and DFT calculations were carried out to identify the favorable binding conformations when the top-scored phytoconstituents bind with the PPAR γ receptors compared to the rosiglitazone. Compound AC2 interacts with the PPAR γ proteins by forming seven hydrogen bonds with the amino acid residues Phe282, His449, Tyr327, His323, and Ser289. The ligand was bound to the protein during the simulation since none of the complex conformations was unstable, and no unfolding or folding occurred. Our results provided an approach to further design and optimize the natural product-inspired small druglike molecules as potential antidiabetic agents. This study highlighted that the phytoconstituents of Allamanda cathartica have antidiabetic potential through the binding of PPAR γ , α -amylase and α -glucosidase proteins that can be further explored for novel antidiabetic drug development. The ethyl acetate extract of A. cathartica displayed significant α -amylase inhibition compared to other fractions, reaching its peak inhibition at a concentration of 4 mg/mL. The organic extract prominently inhibited the enzyme α -glucosidase compared to other fractions, with maximal inhibition observed at a concentration of 4 mg/mL. Phytoconstituents of Allamanda cathartica have shown antidiabetic potential through the binding of PPAR γ , α -amylase, GLP-1 and α -glucosidase proteins Compound AC2 (1-deoxy-d-mannitol) interacts with the PPAR γ proteins through the formation of 7 hydrogen bonds with the residues Phe282, His449, Tyr327, His323 and Ser289, while compound AC31 (Phytol) forms two hydrogen bonds with His323 and Tyr473 amino acid residues. Compounds AC28 (Octanoic acid) show a better binding affinity for GLP-1 target protein. Compounds AC34 (Quercetin) and AC23 (Kaempferol) show excellent binding affinity for α -amylase and α -glucosidase enzymes. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies are attractive therapeutic agents in a wide range of human disorders that bind specifically to their target through their complementary‐determining regions (CDRs). Small proteins with structurally preserved CDRs are promising antibodies mimetics. In this in silico study, we presented new antibody mimetics against the cancer marker epidermal growth factor receptor (EGFR) created by the CDRs grafting technique. Ten potential graft acceptor sites that efficiently immobilize the grafted CDR loops were selected from three small protein scaffolds using a computer. The three most involved CDR loops in antibody‐receptor interactions extracted from panitumumab antibody against the EGFR domain III crystal structure were then grafted to the selected scaffolds through the loop randomization technique. The combination of three CDR loops and 10 grafting sites revealed that three of the 36 combinations showed specific binding to EGFR DIII by binding energy calculations. Thus, the present strategy and selected small protein scaffolds are promising tools in the design of new binders against EGFR with high binding energy. [ABSTRACT FROM AUTHOR]

Thermoplastics have a crystal structure. It has been pointed out that the crystalline structure affects viscoelastic behavior in crystalline polymers, which must be taken into account in MD simulations. In this study the crystalline lamellar structure of Polyethylene (PE) was reproduced via molecular dynamics. To investigate the mechanical behavior and deformation behavior of the lamellar structure of PE, deformation was applied to the model under a constant tensile rate and constant tensile load as tensile and creep analyses, respectively. A tensile analysis indicated localized cracking, and a creep analysis revealed molecular-chain undulation along the tensile direction. To clarify the reason for the difference in deformation distribution between tensile and creep analyses, the potential energy during tensile loading was examined. In the tensile analysis, all the potential energies increased at the start of tension development and decreased rapidly at the break. As revealed in the creep analysis, the bond stretching and bond angle potential energies did not change when deformation started at a strain of approximately 0.20. These results indicated that the deformation behavior depended on the loading configuration, such as tensile and creep loading, and that deformation behaviors vary because of differences in displacement distribution and potential energy. [ABSTRACT FROM AUTHOR]

The insulin superfamily proteins (ISPs), in particular, insulin, IGFs and relaxin proteins are key modulators of animal physiology. They are known to have evolved from the same ancestral gene and have diverged into proteins with varied sequences and distinct functions, but maintain a similar structural architecture stabilized by highly conserved disulphide bridges. The recent surge of sequence data and the structures of these proteins prompted a need for a comprehensive analysis, which connects the evolution of these sequences (427 sequences) in the light of available functional and structural information including representative complex structures of ISPs with their cognate receptors. This study reveals (a) unusually high sequence conservation of IGFs (>90 % conservation in 184 sequences) and provides a possible structure‐based rationale for such high sequence conservation; (b) provides an updated definition of the receptor‐binding signature motif of the functionally diverse relaxin family members (c) provides a probable non‐canonical C‐peptide cleavage site in a few insulin sequences. The high conservation of IGFs appears to represent a classic case of resistance to sequence diversity exerted by physiologically important interactions with multiple partners. We also propose a probable mechanism for C‐peptide cleavage in a few distinct insulin sequences and redefine the receptor‐binding signature motif of the relaxin family. Lastly, we provide a basis for minimally modified insulin mutants with potential therapeutic application, inspired by concomitant changes observed in other insulin superfamily protein members supported by molecular dynamics simulation. [ABSTRACT FROM AUTHOR]

Abstract Heat shock protein 90 (Hsp90), a molecular chaperone, contributes to the preservation of folding, structure, stability, and function proteins. In this study, novel compounds comprising isoxazole structure were designed, synthesized and their potential ability as Hsp90 inhibitors was validated through docking studies. The active site-based compounds were prepared through a multi-step synthesis process and their chemical structures were characterized employing FT-IR, NMR, and mass spectrometry analysis. Cytotoxic and Hsp90 inhibition activities of synthesized compounds were assessed by MTT assay and ELISA kit, respectively. Based on the obtained results, compound 5 exhibited the highest cytotoxicity (IC50; 14 µM) against cancer cells and reduced Hsp90 expression from 5.54 ng/mL in untreated (normal cells) to 1.56 ng/mL in cancer cells. Moreover, molecular dynamics (MD) simulation results indicated its high affinity to target protein and approved its excellent stability which is essential for exerting an inhibitory effect on cancer cell proliferation.

Abstract This work investigates the efficiency of green-synthesized WO3 nanoflakes for the removal of methylene blue dye. The synthesis of WO3 nanoflakes using Hyphaene thebaica fruit extract results in a material with a specific surface area of 13 m2/g and an average pore size of 19.3 nm. A combined theoretical and experimental study exhibits a complete understanding of the MB adsorption mechanism onto WO3 nanoflakes. Adsorption studies revealed a maximum methylene blue adsorption capacity of 78.14 mg/g. The pseudo-second-order model was the best to describe the adsorption kinetics with a correlation coefficient (R2) of 0.99, suggesting chemisorption. The intra-particle diffusion study supported a two-stage process involving surface adsorption and intra-particle diffusion. Molecular dynamic simulations confirmes the electrostatic attraction mechanism between MB and the (002) WO3 surface, with the most favorable adsorption energy calculated as -0.68 eV. The electrokinetic study confirmed that the WO3 nanoflakes have a strongly negative zeta potential of -31.5 mV and a uniform particle size of around 510 nm. The analysis of adsorption isotherms exhibits a complex adsorption mechanism between WO3 and MB, involving both electrostatic attraction and physical adsorption. The WO3 nanoflakes maintained 90% of their adsorption efficiency after five cycles, according to the reusability tests.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, with aldose reductase playing a critical role in the pathophysiology of diabetic complications. This study aimed to investigate the efficacy of flavonoid compounds as potential aldose reductase inhibitors using a combination of molecular docking and molecular dynamics (MD) simulations. The three-dimensional structures of representative flavonoid compounds were obtained from PubChem, minimized, and docked against aldose reductase using Discovery Studio’s CDocker module. The top 10 compounds Daidzein, Quercetin, Kaempferol, Butin, Genistein, Sterubin, Baicalein, Pulchellidin, Wogonin, and Biochanin_A were selected based on their lowest docking energy values for further analysis. Subsequent MD simulations over 100 ns revealed that Daidzein and Quercetin maintained the highest stability, forming multiple conventional hydrogen bonds and strong hydrophobic interactions, consistent with their favorable interaction energies and stable RMSD values. Comparative analysis of hydrogen bond interactions and RMSD profiles underscored the ligand stability. MMPBSA analysis further confirmed the significant binding affinities of Daidzein and Quercetin, highlighting their potential as aldose reductase inhibitors. This study highlights the potential of flavonoids as aldose reductase inhibitors, offering insights into their binding interactions and stability, which could contribute to developing novel therapeutics for DM complications.

Abstract Bioconjugation is one of the most promising strategies to improve drug delivery, especially in cancer therapy. Biomolecules such as bile acids (BAs) have been intensively explored as carriers, due to their peculiar physicochemical properties and biocompatibility. BAs trafficking is regulated by intracellular lipid-binding proteins and their transport in the liver can be studied using chicken liver Bile Acid-Binding Proteins (cL-BABPs) as a reference model. Therefore, we conceived the idea of developing a BA-conjugate with Mirin, an exonuclease inhibitor of Mre11 endowed with different anticancer activities, to direct its transport to the liver. Following computational analysis of various BAs in complex with cL-BABP, we identified cholic acid (CA) as the most promising candidate as carrier, leading to the synthesis of a novel bioconjugate named CA-M11. As predicted by computational data and confirmed by X-ray crystallographic studies, CA-M11 was able to accommodate into the binding pocket of BABP. Hence, it can enter BAs trafficking in the hepatic compartment and here release Mirin. The effect of CA-M11, evaluated in combination with varying concentrations of Doxorubicin on HepG2 cell line, demonstrated a significant increase in cell mortality compared to the use of the cytotoxic drug or Mirin alone, thus highlighting chemo-sensitizing properties. The promising results regarding plasma stability for CA-M11 validate its potential as a valuable agent or adjuvant for hepatic cancer therapy.

Abstract Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-β-D-glucopyranoside, and limonin 17-O-β-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-β-D-glucopyranoside and limonin 17-O-β-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-β-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-β-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism.

The function of cellobiose dehydrogenase (CDH) in biosensors, biofuel cells, and as a physiological redox partner of lytic polysaccharide monooxygenase (LPMO) is based on its role as an electron donor. Before donating electrons to LPMO or electrodes, an interdomain electron transfer from the catalytic FAD-containing dehydrogenase domain to the electron shuttling cytochrome domain of CDH is required. This study investigates the role of two crucial amino acids located at the dehydrogenase domain on domain interaction and interdomain electron transfer by structure-based engineering. The electron transfer kinetics of wild-type Myriococcum thermophilum CDH and its variants M309A, R698S, and M309A/R698S were analyzed by stopped-flow spectrophotometry and structural effects were studied by small-angle X-ray scattering. The data show that R698 is essential to pull the cytochrome domain close to the dehydrogenase domain and orient the heme propionate group towards the FAD, while M309 is an integral part of the electron transfer pathway - its mutation reducing the interdomain electron transfer 10-fold. Structural models and molecular dynamics simulations pinpoint the action of these two residues on the domain interaction and interdomain electron transfer.

This study investigates the dynamics of ice crystal growth and stress distribution in nanoconfined spaces using molecular dynamics simulations. First, the interaction between the pore wall and coarse‐grained water is modified, leading to the development of pore models with varying wettability. Subsequently, the process of ice crystal growth within pores of 10 nm diameter is examined under different temperatures and hydrophobicity conditions. Results unveil that ice crystal growth induces substantial energy and enthalpy alterations within the system. Hydrophobic nanopores demonstrate a protective function by limiting ice crystal growth and water transport, thereby mitigating freezing damage. However, hydrophobic nanopores exhibit increased stress levels when saturated with water. The study employs the Zener pinning theory and mass transfer rates to qualitatively scrutinize the thermodynamic and kinetic interplay between the ice crystal interface and the degree of supercooling. These findings offer insights into the mechanisms of ice formation and stress evolution in nanoconfined environments. [ABSTRACT FROM AUTHOR]

The insulin‐degrading enzyme (IDE) plays a significant role in the degradation of the amyloid beta (Aβ), a peptide found in the brain regions of the patients with early Alzheimer's disease. Adenosine triphosphate (ATP) allosterically regulates the Aβ‐degrading activity of IDE. The present study investigates the electrostatic interactions between ATP‐IDE at the allosteric site of IDE, including thermostabilities/flexibilities of IDE residues, which have not yet been explored systematically. This study applies the quantum mechanics/molecular mechanics (QM/MM) to the proposed computational model for exploring electrostatic interactions between ATP and IDE. Molecular dynamic (MD) simulations are performed at different temperatures for identifying flexible and thermostable residues of IDE. The proposed computational model predicts QM/MM energy‐minimised structures providing the IDE residues (Lys530 and Asp385) with high binding affinities. Considering root mean square fluctuation values during the MD simulations at 300.00 K including heat‐shock temperatures (321.15 K and 315.15 K) indicates that Lys530 and Asp385 are also the thermostable residues of IDE, whereas Ser576 and Lys858 have high flexibilities with compromised thermostabilities. The present study sheds light on the phenomenon of biological recognition and interactions at the ATP‐binding domain, which may have important implications for pharmacological drug design. The proposed computational model may facilitate the development of allosteric IDE activators/inhibitors, which mimic ATP interactions. [ABSTRACT FROM AUTHOR]

Void is a common defect in the preparation of FeCrNiCoCu high - entropy alloy. Thus, this paper employs molecular dynamic simulation to build FeCrNiCoCu models with void for uniaxial tension simulation, and explores the effect of the voids location, void radius and deformation temperature on the mechanical properties. It is found that the void in the crystal with the Z -axis orientation of [111] and at the grain-boundary(GB) will seriously reduce the yield strain and yield stress, but have little effect on the Young's modulus of the model. With the increase of the void radius at the grain boundary, in the elastic stage, the increase of the void radius increases the area of stress concentration, which is conducive to dislocation nucleation, and the mechanical proper- ties of the model decrease accordingly. In the plastic deformation stage, with the increase of the void radius, the initial dislocations tend to expand to the crystal with the Z axis orientation of [001]. The model maintains good mechanical properties at medium and low temperatures; at high temperature, the mechanical properties decrease significantly. In the high temperature plastic deformation stage, the total length of dislocation in the model is low, and the average flow stress is also low. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of a methanolic extract derived from the oleo-gum resin of Commiphora mukul resulted in the isolation of seven pregnene-type steroids (1 - 7), including a new compound named commukulsterol A (1). Their structures were decided by extensive analyses of 1D, 2D-NMR and Mass spectra. The relative configurations of commukulsterols A (1) and B (2) were determined via DFT calculations of their 1H and 13C chemical shifts, followed by DP4+ statistical analysis. Absolute configurations were then decided by biogenetic similarities and specific rotations. Such analyses led to the revision of the structure of 2 , initially elucidated as 20 S -acetyloxy-4-pregnene-3,16-dione, to pro-20 R. 1 - 7 showed varying inhibitory effects on LPS-induced NO release in RAW264.7 macrophages, with IC 50 values ranging from 7.6 to 53.9 μM for (1 - 6) , while 7 didn't show activity up to 100 μM. On the other hand, molecular docking revealed that 3 & 4 could bind to the catalytic site of inducible nitric oxide synthase (iNOS). Moreover, molecular dynamics simulation of 3 & 4 in association with iNOS were examined for 200 ns, revealing adequate stability. ADMET analysis indicated good oral bioavailability and drug-like properties. The observed chemical profile highlighted a unique chemical relationship between Burseraceae and Simaroubaceae families. [Display omitted] • Seven pregnane steroids were isolated from the oleo gum resin of Commiphora muckul. • A new compound and revised structure of a known compound were decided. • Structures were identified by NMR & MS, while configurations by DFT calculations. • Compounds were tested for their anti-inflammatory activity and ADMET properties were predicted. • Molecular docking asserted by molecular dynamics evaluated the activity on molecular level. [ABSTRACT FROM AUTHOR]

To increase the electrical conductivity of nickel electrodes used in solar cells, this study investigated the effects of six different alcohol-based brighteners on nickel electrodeposition and elucidated their mechanisms during the deposition process. Nickel electrodeposition was conducted on a single-crystal silicon (c-Si) substrate in a Watts nickel plating bath with the addition of various additives at 1 g/L. Surface analysis and microstructure characterization were employed, alongside density functional theory calculations and molecular dynamics simulations, to analyze the influence of brightener molecule adsorption on metal grain growth and conductivity properties. These results indicate that alcohol-based additives can be automatically absorbed on the surface of the deposit, whereas long-chain polyhydroxy additives result in a smaller energy gap ( Δ E ) and more active adsorption sites than do short-chain additives, facilitating greater reactivity on the Ni surface. This resulted in a preferred orientation shift of the crystal structure from the (200) plane to the (111) plane, along with a refined grain size and conical morphology growth. Among the studied additives, long-chain molecules increased the Ni0 content in the plating layer and increased its conductivity. In particular, sorbitol effectively reduced the resistivity and grain growth rate of the coating, underscoring its potential as an additive for fabricating high-performance electrodes on c-Si substrates. [ABSTRACT FROM AUTHOR]