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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]

Mycolic acids are the key constituents of mycobacterial cell wall, which protect the bacteria from antibiotic susceptibility, helping to subvert and escape from the host immune system. Thus, the enzymes involved in regulating and biosynthesis of mycolic acids can be explored as potential drug targets to kill Mycobacterium tuberculosis (Mtb). Herein, Kyoto Encyclopedia of Genes and Genomes is used to understand the fatty acid metabolism signaling pathway and integrative computational approach to identify the novel lead molecules against the mtFabH (β-ketoacyl-acyl carrier protein synthase III), the key regulatory enzyme of the mycolic acid pathway. The structure-based virtual screening of antimycobacterial compounds from ChEMBL library against mtFabH results in the selection of 10 lead molecules. Molecular binding and drug-likeness properties of lead molecules compared with mtFabH inhibitor suggest that only two compounds, ChEMBL414848 (C1) and ChEMBL363794 (C2), may be explored as potential lead molecules. However, the spatial stability and binding free energy estimation of thiolactomycin (TLM) and compounds C1 and C2 with mtFabH using molecular dynamics simulation, followed by molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) indicate the better activity of C2 (ΔG = −14.18 kcal/mol) as compared with TLM (ΔG = −9.21 kcal/mol) and C1 (ΔG = −13.50 kcal/mol). Thus, compound C1 may be explored as promising drug candidate for the structure-based drug designing of mtFabH inhibitors in the therapy of Mtb. [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]

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]

[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]

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]