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The exact solution of the Euler equation, which describes the time evolution of a blast wave created by an intense explosion, is a classic problem in gas dynamics. However, it has been found that the analytical results do not match with results from molecular dynamics simulation of hard spheres in two and three dimensions. In this paper, we show that the mismatch between theory and simulations can be resolved by considering the Navier–Stokes equation. From the direct numerical simulation of the Navier–Stokes equation in two and three dimensions, we show that the inclusion of heat conduction and viscosity terms is essential to capture the results from molecular dynamics simulations. [ABSTRACT FROM AUTHOR]

The native function of amyloid-β (Aβ) peptides is still unexplored. However, several recent reports suggest a prominent role of Aβ peptides in acetylcholine homeostasis. To clarify this role of Aβ, we have reported that Aβ peptides at physiological concentrations can directly enhance the catalytic efficiency of the key cholinergic enzyme, choline acetyltransferase (ChAT), via an allosteric interaction. In the current study, we further aimed to elucidate the underlying ChAT-Aβ interaction mechanism using in silico molecular docking and dynamics analysis. Docking analysis suggested two most probable binding clusters on ChAT for Aβ40 and three for Aβ42. Most importantly, the docking results were challenged with molecular dynamic studies of 100 ns long simulation in triplicates (100 ns × 3 = 300 ns) and were analyzed for RMSD, RMSF, RoG, H-bond number and distance, SASA, and secondary structure assessment performed together with principal component analysis and the free-energy landscape diagram, which indicated that the ChAT-Aβ complex system was stable throughout the simulation time period with no abrupt motion during the evolution of the simulation across the triplicates, which also validated the robustness of the simulation study. Finally, the free-energy landscape analysis confirmed the docking results and demonstrated that the ChAT-Aβ complexes were energetically stable despite the unstructured nature of C- and N-terminals in Aβ peptides. Overall, this study supports the reported in vitro findings that Aβ peptides, particularly Aβ42, act as endogenous ChAT-Potentiating-Ligand (CPL), and thereby supports the hypothesis that one of the native biological functions of Aβ peptides is the regulation of acetylcholine homeostasis. [ABSTRACT FROM AUTHOR]

Functionalization of graphene is the best way to create a high degree of dispersion and bonding to polymer matrix in order to obtain high performance composites. The effects of carboxyl (−COOH) functionalized graphene (FG) on the mechanical properties of its epoxy-based nanocomposites have been examined by molecular dynamics (MD) simulations. Simulations cells of nanocomposites with varying wt% of FG (1, 2, and 3 wt%) were constructed using Material Studio 6.0. The MD simulation findings of nanocomposites reveal that they have better mechanical properties such as elastic modulus, bulk modulus, shear modulus, and the Poisson's ratio than pure epoxy. Furthermore, the computational results of nanocomposites have been effectively confirmed with available experimental data. Therefore, the current MD simulation shows a decent computational sign for the existing experimental and simulation outcomes on mechanical properties of FG/epoxy nanocomposites. [ABSTRACT FROM AUTHOR]

Galectin-3 (Gal-3), a β-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139—a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis—is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3. [ABSTRACT FROM AUTHOR]

Transcriptional enhanced associate domain (TEAD) is a family of transcription factors that plays a significant role during embryonic developmental processes, and its dysregulation is responsible for tumour progression. TEAD is considered as druggable targets in various diseases, namely cancer, cardiovascular diseases and neurodegenerative disorders. Previous structural studies revealed the importance of the central hydrophobic pocket of TEAD as a potential target for small-molecule inhibitors and demonstrated flufenamic acid (FLU) (a COX-2 enzyme inhibitor) to bind and inhibit TEAD2 functions. However, to date, no drug candidates that bind specifically to TEAD2 with high selectivity and efficacy have been developed or proposed. Within this framework, we present here a case study where we have identified potential TEAD2 inhibitor candidates by integrating multiple computational approaches. Among the candidates, the top two ranked compounds ZINC95969481 (LG1) which is a fused pyrazole derivative and ZINC05203789 (LG2), a fluorene derivative resulted in much favourable binding energy scores than the reference ligand, FLU. The drug likeliness of the best compounds was also evaluated in silico to ensure the bioavailability of these compounds particularly LG1 as compared to FLU thus providing a strong rationale for their development as leads against TEAD. Molecular dynamics simulations results highlighted the role of key residues contributing to favourable interactions in TEAD2-LG1 complex with much favourable interaction and binding free energy values with respect to the reference compound. Altogether, this study provides a starting platform to be more exploited by future experimental research towards the development of inhibitors against TEAD, a persuasive strategy for therapeutic intervention in cancer treatment. [ABSTRACT FROM AUTHOR]

Cation-intercalated graphene oxide (GO) membrane has emerged as a promising candidate for desalination applications as reverse osmosis (RO) membrane. This study constructs GO membranes with different cations (K+ or Mg2+) and investigates the potential of these membranes in boron removal via nonequilibrium molecular dynamics simulations. In the aquatic environment, boron can exist in the form of boric acid or borate ion, depending on the pH of the solution. As a result, this study considers two forms of boron. This study reveals that the GO membranes effectively reject negatively charged borate ions due to their bigger hydration shell and stronger electrostatic repulsion with the membrane than neutral boric acid molecules. Moreover, K+ ion intercalated GO membranes showed higher boron rejection than Mg2+ ion intercalated GO membranes owing to weaker electrostatic attraction of K+ ions with the boric acid (or borate ions). Additionally, a summary of the effects of oxygen-containing functional groups of the GO membrane on boron rejection is provided. Since the hydroxyl and epoxy functional groups interact with boric acid molecules more strongly, these molecules are prevented from permeating through the membrane. On the other hand, the permeation rate of borate ions declines because of their stronger interactions with the carboxyl functional groups. Furthermore, Mg2+ ion intercalated GO membranes exhibited higher water permeance, excellent Na+ rejection, and poor Cl− rejection compared to K+ ion intercalated GO membranes. • The effects of intercalated cations inside the GO layers on boron rejection are investigated. • GO membranes reject borate ions effectively when compared to boric acid. • The impact of oxygen-containing functional groups of GO membranes on boron rejection is presented. [ABSTRACT FROM AUTHOR]

cis and trans‐copper(II) porphyrin dimers have been synthesized, in which two CuII porphyrin macrocycles are bridged through a rigid ethene linker for possible through‐space and through‐bond spin‐couplings between the paramagnetic CuII centers. It has been found that the two macrocycles come closer after 1 e− oxidation, however, they move far apart upon further 1 e− oxidation leading to transformation of the cis to the trans isomer. Detailed investigations are performed here on the interactions between the two porphyrin macrocycles, between two unpaired spins of closely spaced CuII centers, and also between the unpaired spins of metal and porphyrin π–cation radicals. Spectroscopic investigations along with the X‐ray structure of the 2 e−‐oxidized complex displayed strong electronic communications through the bridge between two porphyrin π–cation radicals. The counterion I9− is stabilized in an unusual trigonal‐pyramidal structure in the 2 e−‐oxidized complex in which the central iodide ion is bound with four iodine (I2) molecules. Variable‐temperature magnetic study revealed strong antiferromagnetic coupling between the two porphyrin π–cation radical spins (Jr–r) in the 2 e−‐oxidized complex. DFT calculations suggest stabilization of the triplet state, which is also in good agreement with the experiment. Ab initio molecular dynamics allowed the variation of the structural details to be followed upon stepwise oxidations and also the final isomerization process including its associated energy barrier. [ABSTRACT FROM AUTHOR]

Simulation of molecular dynamics (MD) allows mimicking the systematic variation of mechanical properties beyond the capacity of experimental methods. In this review, the status of the molecular modelling, simulation and mechanical and thermal characterisation of graphene and the properties of bulk nanocomposites using MD are extensively examined. The molecular models of graphene (pristine and functionalised), and the most common epoxy matrix with preeminent MD energy minimisation tools are thoroughly examined. The presence of MD's simulation setup and the computational procedure for different styles of mixing the polymer matrix with graphene as nanofiller are exhaustively reviewed. In particular, in the analysis of several papers on graphene and their composites, it has been noticed that mechanical, thermal and interfacial properties are ubiquitous to most of the engineering applications. In this review, advances in the molecular modelling and simulation of graphene and their composites has been discussed in detail keeping graphene structures, aspect ratio, weight fraction and density effect as major factors. Finally, the research gaps and future scope are discussed, which indeed helps the researchers in scaling up their researches in graphene and their composites, which may further lead to their experimental findings. [ABSTRACT FROM AUTHOR]

The intramolecular relaxation dynamics of semiflexible dendrimers in dilute solutions are theoretically investigated in the framework of optimized Rouse-Zimm formalism. Semiflexibility is implemented by modeling topological restrictions on the bond directions and orientations of the respective bond-vectors. Based on our recently developed approach for semiflexible dendrimers [A. Kumar and P. Biswas, Macromolecules 43, 7378 (2010)], the mechanical and dielectric relaxation moduli are studied as functions of local flexibility parameters and branching topology. It is rather interesting to observe that semiflexibility affects the local modes of G′′(ω) and Δ[variant_greek_epsilon]′′(ω), which have lower relaxation rate with increasing bond restrictions, while the collective modes with small relaxation rate remain almost constant. The relaxation dynamics of the flexible dendrimer is similar to that of the semiflexible dendrimer with unrestricted bond orientations ([lowercase_phi_synonym] = 0) and is flanked by the compressed ([lowercase_phi_synonym] = 30°) and expanded ([lowercase_phi_synonym] = 150°) conformations, respectively. The effect of semiflexibility is typically reflected in the intermediate frequency regime. The expanded conformations of semiflexible dendrimers display a power-law behavior in the intermediate frequency regime for both loss and storage modulus resembling fractal structures, while the compressed and unrestricted bond orientation conformations exhibit an approximately logarithmic dependence. The power-law exponent is found to be similar to the flexible dendrimers with excluded volume interactions. Thus, by tuning [lowercase_phi_synonym], a spectrum of dynamic relaxation pattern is obtained spanning a broad range of conformations from a power-law fractal network to a non-fractal one. In certain limits, this highly generalized model captures the characteristics of flexible dendrimers and also resembles La Ferla's model semiflexible dendrimers. The influence of hydrodynamic interactions reduces the dynamical range and the width of the intermediate domain by decreasing the smaller relaxation rates and increasing the higher relaxation rates correspondingly. [ABSTRACT FROM AUTHOR]

Molecular Dynamics (MD) simulations were carried out to investigate the effect of functionalization of graphene on glass transition temperature (Tg) of epoxy composites were built using LY556 epoxy resin cross-linked with DETDA. Three different formats of graphene including pristine, with amine (−NH2) groups and carboxyl (−COOH) groups respectively involved in the investigation. The simulation results indicated that Tgof the graphene epoxy composites are higher than that of pure epoxy. Furthermore, Tgof composites randomly embedded with functionalized graphene were lower than that with pristine graphene, and Tgof the composites embedded with COOH-graphene was much lower than that with NH2-graphene. The simulation results of Tgwere in good agreement with experimental results indicating that this computational method can be used to predict effectively the Tgof graphene epoxy composites. [ABSTRACT FROM AUTHOR]

The AB 5 type toxin produced by the Vibrio cholerae bacterium is the causative agent of the cholera disease. The cholera toxin (CT) has been shown to bind specifically to GM1 glycolipids on the membrane surface. This binding of CT to the membrane is the initial step in its endocytosis and has been postulated to cause significant disruption to the membrane structure. In this work, we have carried out a combination of coarse-grain and atomistic simulations to study the binding of CT to a membrane modelled as an asymmetrical GM1-DPPC bilayer. Simulation results indicate that the toxin binds to the membrane through only three of its five B subunits, in effect resulting in a tilted bound configuration. Additionally, the binding of the CT can increase the area per lipid of GM1 leaflet, which in turn can cause the membrane regions interacting with the bound subunits to experience significant bilayer thinning and lipid tail disorder across both the leaflets. [ABSTRACT FROM AUTHOR]

Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism. [ABSTRACT FROM AUTHOR]

In Gram-negative bacteria, outer-membrane protein channels, such as OmpF of Escherichia coli, constitute the entry point of various classes of antibiotics. While antibacterial research and development is declining, bacterial resistance to antibiotics is rising and there is an emergency call for a new way to develop potent antibacterial agents and to bring them to the market faster and at reduced cost. An emerging strategy is to follow a bottom-up approach based on microscopically founded computational based screening, however such strategy needs better-tuned methods. Here we propose to use molecular dynamics (MD) simulations combined with the metadynamics algorithm, to study antibiotic translocation through OmpF at a molecular scale. This recently designed algorithm overcomes the time scale problem of classical MD by accelerating some reaction coordinates. It is expected that the initial assumption of the reaction coordinates is a key determinant for the efficiency and accuracy of the simulations. Previous studies using different computational schemes for a similar process only used one reaction coordinate, which is the directionality. Here we go further and see how it is possible to include more informative reaction coordinates, accounting explicitly for: (i) the antibiotic flexibility and (ii) interactions with the channel. As model systems, we select two compounds covering the main classes of antibiotics, ampicillin and moxifloxacine. We decipher the molecular mechanism of translocation of each antibiotic and highlight the important parameters that should be taken into account for improving further simulations. This will benefit the screening and design for antibiotics with better permeation properties. [ABSTRACT FROM AUTHOR]

The properties of lipid bilayers in contact with trehalose solutions in water were studied in the full concentration range using molecular dynamics simulations. The mechanism of trehalose interaction with the bilayer surface was analysed considering hydrogen bonding and molecular arrangements as well as the possible changes in bilayer properties. The effect of concentration of the possible mechanisms of trehalose action as membrane protectant were discussed to infer the possible evolution of water replacement by trehalose at the membrane surface and its relationship with the trehalose role in anhydrobiosis and drying processes. Unlabelled Image • Anhidrobiosis in presence of trehalose • Trehalose solution in presence interacting with lipid membranes • Water replacement mechanisms • Intermolecular forces at lipid bilayer interfaces • Nanoscopic characterization of bilayer structuring upon water replacement [ABSTRACT FROM AUTHOR]

The properties of trehalose + water mixtures are studied as a function of mixture composition and temperature using molecular dynamics simulations. As trehalose disaccharide has been proposed for dry preservation purposes, the objective of this work is to analyse the nanoscopic properties of the considered mixtures, in terms of aggregation, clustering, interactions energies, and local dynamics, and their relationships with hydrogen bonding. The reported results allow a detailed characterization of hydrogen bonding and its evolution with mixture composition and thus inferring the effects of trehalose on water structuring providing results to justify the mechanisms of trehalose acting as preservation agent. [ABSTRACT FROM AUTHOR]

The study of the ability of drug molecules to enter cells through the membrane is of vital importance in the field of drug delivery. In cases where the transport of the drug molecules through the membrane is not easily accomplishable, other carrier molecules are used. Spherical fullerene molecules have been postulated as potential carriers of highly hydrophilic drugs across the plasma membrane. Here, we report the coarse-grain molecular dynamics study of the translocation of C60 fullerene and its derivatives across a cell membrane modeled as a 1,2-distearoyl-sn-glycero-3-phosphocholine bilayer. Simulation results indicate that pristine fullerene molecules enter the bilayer quickly and reside within it. The addition of polar functionalized groups makes the fullerenes less likely to reside within the bilayer but increases their residence time in bulk water. Addition of polar functional groups to one half of the fullerene surface, in effect creating a Janus particle, offers the most promise in developing fullerene models that can achieve complete translocation through the membrane bilayer. [ABSTRACT FROM AUTHOR]

Carbon nanotubes have been proposed as an ideal reinforcement for the fabrication of nanocomposites. However, because of their chemical inertness, carbon nanotubes have to be functionalized in order to acquire superior properties. In the present paper, we examine the effect of functionalization of single-, double-, and triple-walled carbon nanotubes with ethylene-di-amine, analyzing their elastic properties. Condensed-phase optimized molecular potentials for atomistic simulations studies force field is used to model the interatomic interactions for armchair (5,5), (9,0), and (10,10) configuration carbon nanotubes. Molecular dynamics simulations for carbon nanotubes with various densities of the attached ethylene-di-amine molecules have been performed. This study quantitatively investigates the effect of amine functionalization (up to 12 numbers of ethylene-di-amine groups) on the Young's, bulk, and shear moduli and tensile strengths of different carbon nanotube structures. [ABSTRACT FROM AUTHOR]

[Display omitted] • Spectral methods have been used to investigate the interaction of R1 with HHb and BSA. • Thermodynamic parameters suggested exothermic spontaneous binding processes involving hydrogen bonding and van der Waal interaction. • Molecular docking and molecular dynamics have been utilized to discuss the principle binding sites of proteins for R1. • R1 proposes preferentially binding to the hydrophobic cavity in site III of proteins. A Rhodamine-based fluorescent probe R1 has been successfully utilized to detect BSA and HHb proteins via non-covalent bonding. The protein binding nature with R1 has been unravelled by the characteristic changes in absorption, emission and circular dichroism spectra that indicated their noticeable interaction. The experimental results have also shown the moderate strength between proteins and R1 from the quenching of proteins through the static quenching mechanism. The hyperchromism in the absorption band of proteins with R1 has given vital information and binding affinity values have been calculated from Stern-Volmer plots. The calculated values of the thermodynamic parameters revealed a spontaneous binding processes occurring primarily via hydrogen bonding and van der Waal interactions. Furthermore, in-silico approaches have been utilized to make a comparison and conclusion with spectroscopic results. The outcome of these studies could be useful to examine the drug-protein binding for further exploitation. [ABSTRACT FROM AUTHOR]

Xanthine oxidase (XO) plays a critical role in purine catabolism, catalyzing the conversion of hypoxanthine to xanthine and xanthine to uric acid, contributing to superoxide anion production. This process is implicated in various human diseases, particularly gout. Traditional XO inhibitors, such as allopurinol and febuxostat, while effective, may present side effects. Our study focuses on Asphodelus microcarpus , a plant renowned for traditional anti-inflammatory uses. Recent investigations into its phenolic-rich flowers, notably abundant in luteolin derivatives, reveal its potential as a natural source of XO inhibitors. In the present research, XO inhibition by an ethanolic flowers extract from A. microcarpus is reported. In silico docking studies have highlighted luteolin derivatives as potential XO inhibitors, and molecular dynamics support that luteolin 7- O -glucoside has the highest binding stability compared to other compounds and controls. In vitro studies confirm that luteolin 7- O -glucoside inhibits XO more effectively than the standard inhibitor allopurinol, with an IC 50 value of 4.8 μg/mL compared to 11.5 μg/mL, respectively. These findings underscore the potential therapeutic significance of A. microcarpus in managing conditions related to XO activity. The research contributes valuable insights into the health-promoting properties of A. microcarpus and its potential application in natural medicine, presenting a promising avenue for further exploration in disease management. • A. microcarpus flower extract inhibits xanthine oxidase (XO) via mixed-type inhibition. • Luteolin-7- O -glucoside stably binds XO in AutoDock and 250ns molecular dynamics. • Luteolin 7- O -glucoside demonstrates in vitro XO inhibition (IC 50 4.8 μg/mL). [ABSTRACT FROM AUTHOR]

Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14∶0/0∶0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16∶0/0∶0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14∶0/0∶0) and PC(16∶0/0∶0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS. [ABSTRACT FROM AUTHOR]

We rationalize how fluorite-structured CeO2, which is crystallographically isotropic, can grow anisotropically (without templates) to form nanoparticles, rods, and cubes. In particular, single-crystalline and monodispersed cubic CeO2 nanoparticles, nanorods, and nanocubes have been selectively synthesized by a very simple, efficient, and economical hydrothermal process using different NaOH concentrations, and Ce(NO3)3 as the cerium precursor. High-resolution transmission electron microscopy reveals nanomaterials with differently exposed crystal planes: {111} and {100} for nanoparticles, {110} and {100} for nanorods, and {100} for nanocubes. During the preparation of the CeO2 nanomaterials, the formation of intermediate anisotropic Ce(OH)3 species under basic conditions and their conversion into CeO2 at higher temperature are key factors responsible for the shape evolution. Atomistic computer simulations were used to help rationalize how the synthetic conditions impact upon the morphology of the nanomaterial. The synthesized CeO2 nanoparticles and nanorods demonstrate higher catalase mimetic activities than the nanocubes. [ABSTRACT FROM AUTHOR]

Microtubule-associated serine/threonine kinase-like (MASTL) (or Greatwall kinase (GWL)) is an important cell cycle regulating kinase that regulates the G2-M transition. Uncontrolled MASTL activity is implicated in breast cancer progression. To date, very few inhibitors have been reported against this protein. Here, structure-based computational modeling indicates that the natural product flavopiridol (FLV) binds strongly to MASTL and these results are validated using molecular dynamics simulation studies. An in vitro kinase assay reveals an EC 50 (effective concentration) value of FLV to be 82.1 nM and a better IC 50 compared to the positive reference compound, staurosporine. FLV is found to inhibit MASTL kinase activity, arresting the cell growth in the G1 phase and inducing apoptosis in breast cancer cells. Consistent with these results differential gene expression obtained using RNA sequencing studies, and validated by RT PCR and immunoblot analysis, indicate that MASTL inhibition induces cell cycle arrest and apoptotic-related genes. Furthermore, metastasis- and inflammation-related genes are downregulated. Thus, the deregulation of MASTL signaling pathways on targeted inhibition of its kinase activity is revealed. This study lays a strong foundation for investigating FLV as a lead compound in breast cancer therapeutics. • Microtubule-associated serine/threonine kinase-like (MASTL) is an important drug target in breast cancer that regulates G2-M transition. • Flavopiridol-mediated inhibition of MASTL kinase activity causes G1 arrest resulting in apoptosis. • Various metastasis and inflammation-related genes are differentially regulated on MASTL inhibition. [ABSTRACT FROM AUTHOR]

• First structure of a two-domain M1 peptidase lacking C-terminal domain. • Activity despite lack of domain with gating and substrate specificity roles. • Substrate-bound structure reported at 1.9 Å resolution. • Structural features enabling efficient catalysis with only two domains revealed. Zinc metallopeptidases of the M1 family (M1 peptidases) with unique metal binding motif HEXXH(X) 18 E regulate many important biological processes such as tumor growth, angiogenesis, hormone regulation, and immune cell development. Typically, these enzymes exist in three-domain [N-terminal domain (N-domain), catalytic domain, and C-terminal domain (C-domain)] or four-domain (N-domain, catalytic domain, middle domain, and C-domain) format in which N-domain and catalytic domain are more conserved. The C-domain plays important roles in substrate binding and gating. In this study we report the first structure of a two-domain (N-domain and catalytic domain) M1 peptidase at 2.05 Å resolution. Despite the lack of C-domain, the enzyme is active and prefers peptide substrates with large hydrophobic N-terminal residues. Its substrate-bound structure was determined at 1.9 Å resolution. Structural analyses supported by site directed mutagenesis and molecular dynamics simulations reveal structural features that could compensate for the lack of C-domain. A unique loop insertion (loop A) in the N-domain has important roles in gating and desolvation of active site. Three Arg residues of the catalytic domain are involved in substrate-binding roles typically played by positively charged residues of C-domain in other M1 peptidases. Further, its unique exopeptidase sequence motif, LALET, creates a more hydrophobic environment at the S1 subsite (which binds N-terminal residue of the substrate in aminopeptidases) than the more common GXMEN motif in the family. This leads to high affinity for large hydrophobic residues in the S1 subsite, which contributes towards efficient substrate binding in absence of C-domain. [ABSTRACT FROM AUTHOR]

Deep eutectic solvents, a new genre of green solvent, easy to synthesize, low volatility and non-toxic in nature, emerged as an efficient extractant for denitrogenation. We have performed a molecular dynamics simulation study to investigate the role of glyceline as an extractant for removal of nitrogen impurities namely indole, pyrrole, pyridine, and quinoline from a model liquid fuel. Δ G transfer was evaluated to capture the thermodynamic feasibility of the transfer of nitrogen impurities from the fuel to the glyceline phase. Negative value of Δ G transfer was obtained for the nitrogen impurities, and the partition coefficient in the following order: indole > pyrrole > quinoline > pyridine. The simulation revealed that the chloride-ion possesses strong interaction with indole and pyrrole while glycerol favors quinoline and pyridine. The fuel phase was observed to be free from impurities while glyceline phase contained impurities, which was confirmed by the negative and positive values of Δ G transfer and partition coefficient respectively. The self-diffusion coefficient for indole was observed to be the lowest while pyridine possesses the highest value, which was found to be in agreement with the observations from radial and spatial distribution functions. Further, this understanding at the atomic level for liquid-liquid extraction will help in developing potential solvents for denitrogenation of liquid fuel. • A negative value of Δ G transfer indicates the thermodynamically favorable separation. • Trend of the partition coefficient follows indole > pyrrole > quinoline > pyridine. • Lowest and highest D self values were observed for indole and pyridine respectively. • Phase separation between fuel oil and deep eutectic solvent was clearly observed. [ABSTRACT FROM AUTHOR]

The cover pictue shows a morphological phase diagram of CeO2 indicating regions of nanoparticle nanorod and nanocube formation after certain time periods of hydrothermal treatment. The phase boundaries are estimated by using experimental parameters (NaOH concentration (M), temperature (°C), and time (h)) of the hydrothermal process. The phase boundaries from nanoparticles to nanorods and nanocubes are observed to shift at higher temperature with low caustic concentration. The relative incremental increase in temperature suggests that nanorod and nanocube formation is more dependent on temperature than caustic concentration. Inset is the atomic simulation of nanostructured materials showing the growth direction. Details of this study are given in the Full Paper at page 1446 ff. by S. Seal and co‐workers. [ABSTRACT FROM AUTHOR]

A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC 50 value of 30.3 μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data. [ABSTRACT FROM AUTHOR]

Neisseria gonorrhoeae have progressively developed resistance to almost all antibiotics, and it has become imperative to develop novel approaches to combat its multi-drug resistance. Overexpression of the MtrCDE, an RND family efflux pump, is one of the primary causes of antibiotic resistance in the gonococcus and is considered an important target for combating anti-microbial resistance. PaβN, D13–9001, and other EPIs are identified to target the RND efflux pumps, but due to their cytotoxicity, they have failed in clinical trials. Herein, an extensive pharmacophore-based approach was performed to identify novel EPI inhibitors with improved pharmacology/safety profiles. An integrated computational framework comprising pharmacophore generation, virtual screening using HTVS, SP and XP Glide methodology, MM-GBSA analysis, Induced fit docking, QPLD, DFT, ADMET properties calculation, Molecular Dynamics, and MM-PBSA analysis was performed. The comprehensive study leads to the identification of five non-toxic bioactive compounds, namely - ZINC000008764610, ZINC000030879142, ZINC000030879358, ZINC000253414904, and ZINC000225394671, as potential EPIs for RND efflux pump of Neisseria gonorrhoeae. The five compounds were selected based on the pharmacophore mapping, higher dock score than the known EPIs, binding stability, molecular interactions with the critical residues of MtrD protein, higher ADMET properties, non-toxicity, and free energy estimations. In summary, the analysis led to the identification of five top hits from the natural compound subset of the ZINC database that has a higher binding affinity to the MtrD and adequate physiochemical/pharmacokinetic profile that can be used for the generation of novel EPIs against Neisseria gonorrhoeae. [Display omitted] • Neisseria gonorrheae have shown high multi-drug resistance & needs to be tackled on urgent basis. • Efflux pumps are novel drug targets that can potentiates the use of antibiotics against pathogens. • An extensive pharmacophore based screening was performed to identify novel EPIs for N. gonorrheae. • The lead molecules showed strong binding interactions with the active-site residues of MtrD Ng. • These lead molecules can be used to develop therapeutics for N. gonorrheae caused gonorrhea. [ABSTRACT FROM AUTHOR]

We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10−5, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10−8, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10−3, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10−22) and protection (*11, OR = 0.8, Pc = 2.7×10−2, *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10−16, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10−4 and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10−4). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis is the formation of new blood vessels from existing blood vessels and is critical for many physiological and pathophysiological processes. In this study we have shown the unique property of cerium oxide nanoparticles (CNPs) to induce angiogenesis, observed using both in vitro and in vivo model systems. In particular, CNPs trigger angiogenesis by modulating the intracellular oxygen environment and stabilizing hypoxia inducing factor 1α endogenously. Furthermore, correlations between angiogenesis induction and CNPs physicochemical properties including: surface Ce3+/Ce4+ ratio, surface charge, size, and shape were also explored. High surface area and increased Ce3+/Ce4+ ratio make CNPs more catalytically active towards regulating intracellular oxygen, which in turn led to more robust induction of angiogenesis. Atomistic simulation was also used, in partnership with in vitro and in vivo experimentation, to reveal that the surface reactivity of CNPs and facile oxygen transport promotes pro-angiogenesis. [Copyright &y& Elsevier]