Cancer poses a significant global health challenge due to its high mortality rate and complex treatment strategies. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), which is notably overexpressed in various malignancies, represents a promising target for anticancer drug development. Furanpydone A, a new 4-hydroxy-2-pyridone alkaloid isolated from the endophytic fungus Arthrinium sp. GZWMJZ-606, has shown potent inhibitory activity against several cancer cell lines. This study provides the first computational evaluation of furanpydone A, focusing on its potential inhibition of MTHFD2 through molecular docking and 200 ns molecular dynamics (MD) simulations. Molecular docking revealed a binding free energy of -8.08 kcal/mol for furanpydone A, comparable to the control compound DS44960156 (-8.13 kcal/mol), indicating stable interactions with the MTHFD2 active site. MD simulations confirmed the structural stability of the furanpydone A-MTHFD2 complex, with RMSD values ranging from 1.5 to 2.9 Å, RMSF values below 4 Å, and a radius of gyration (Rg) of 26.7 Å. Furanpydone A maintained approximately four consistent hydrogen bonds throughout the simulation. Analysis of furanpydone A binding pose orientations and interactions with the MTHFD2 enzyme at 0 ns, 40 ns, 80 ns, 120 ns, 160 ns, and 200 ns revealed consistent and stable binding. MM-PBSA analysis showed a binding free energy (ΔGbind) of -23.57 ± 0.13 kcal/mol, with electrostatic and van der Waals interactions contributing significantly, suggesting competitive binding affinity to the control compound (-25.32 ± 0.11 kcal/mol). The contribution of individual amino acid residues, including key residues such as ARG43, TYR84, ASN87, LYS88, GLN132, and PRO314, indicated strong interactions that support the stability of the furanpydone A-MTHFD2 complex. ADMET predictions indicated that furanpydone A met key drug-likeness criteria and demonstrated good oral bioavailability, suitable distribution profile, minimal risk of drug-drug interactions, efficient elimination, and low toxicity potential. These findings suggest that furanpydone A is a promising candidate for cancer treatment, warranting further in vitro and in vivo validation, and highlighting its potential impact on the development of new anticancer therapies.

Numerous side effects of breast cancer drugs have prompted researchers to explore more into new therapeutic approaches derived from natural substances. In this context, our study focused on uncovering the potential of East Kalimantan propolis from Trigona apicalis for breast cancer treatment including the underlying mechanisms through bioinformatics approached. We conducted integrated in vitro and bioinformatics analysis of network pharmacology, molecular docking, molecular dynamics and MM-GBSA analysis. Initially, in vitro cytotoxic assay demonstrated the anti-breast cancer activity potential of ethanol extract of East Kalimantan propolis, particularly its ethyl acetate fraction, which exhibited similar activity to doxorubicin, as indicated by their IC50 value. This study revealed eight propolis compounds, consisting of flavonoids and phenolic acids, in East Kalimantan propolis. By integrating microarray datasets (GSE29431, GSE36295, and GSE42568) analysis with potential targets derived from propolis compounds, 39 shared target genes were identified. Subsequently, GO and KEGG pathway, protein-protein interaction (PPI) network, core hub genes and gene expression analysis revealed three major targets, namely, PTGS2, CXCL2, and MMP9. Among them, only MMP9 was highly expressed in breast cancer than normal. Moreover, molecular docking revealed the six of propolis compounds which exhibited pronounced binding affinity towards MMP-9, better than marimastat as control drug. Dynamic simulation confirmed the stability of chrysin and quercetin as best compounds. Additionally, MM-GBSA analysis revealed a relative binding energy for chrysin (-25.6403 kcal/mol) that was comparable to marimastat (-27.3827 kcal/mol). In conclusion, this study reveals how East Kalimantan Propolis affect breast cancer and emphasizes MMP9 as a key target for future therapeutics.

Here, we report new 2-nitro and/or 4-trifluoromethylphenyl-based small molecules developed as inhibitors of alpha-Syn fibril formation. The set of eighteen compounds was inspired by well-known alpha-Syn aggregation modulators retrieved from literature. The preliminary biochemical data suggested that the two molecules out of eighteen compounds exerted activity comparable to that of reference compound SynuClean-D (SC-D, 5-nitro-6-(3-nitrophenyl)-2-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonitrile), according to Thioflavin T kinetics. Pharmacophore modelling deciphered the main structural requirements for alpha-Syn aggregation modulators. Moreover, docking and molecular dynamics simulations depicted the binding mode with the targeted alpha-Syn fibrils. The structural data of these new potential α-Syn binders might furnish additional information for understanding the mechanism of action of the ligands that specifically target the NAC domain as theranostic agents for α-synucleopathies.

Metal matrix composites (MMCs) combine metal with ceramic reinforcement, offering high strength, stiffness, corrosion resistance, and low weight for diverse applications. Al-SiC, a common MMC, consists of an aluminum matrix reinforced with silicon carbide, making it ideal for the aerospace and automotive industries. In this work, molecular dynamics simulations are performed to investigate the mechanical properties of the complex-shaped models of Al-SiC. Three different volume fractions of SiC particles, precisely 10%, 15%, and 25%, are investigated in a composite under uniaxial tensile loading. The tensile behavior of Al-SiC composites is evaluated under two loading directions, considering both cases with and without diffusion effects. The results show that diffusion increases the ultimate tensile strength of the Al-SiC composite, particularly for the 15% SiC volume fraction. Regarding the shape of the SiC particles considered in this research, the strength of the composite varies in different directions. Specifically, the ultimate strength of the Al-SiC composite with 25% SiC reached 11.29 GPa in one direction, and 6.63 GPa in another, demonstrating the material\'s anisotropic mechanical behavior when diffusion effects are considered. Young\'s modulus shows negligible change in the presence of diffusion. Furthermore, diffusion improves toughness in Al-SiC composites, resulting in higher values compared to those without diffusion, as evidenced by the 25% SiC volume fraction composite (2.086 GPa) versus 15% (0.863 GPa) and 10% (1.296 GPa) SiC volume fractions.

Interleukin (IL)-33, a member of the IL-1 cytokine family, plays a vital role in immune system regulation and inflammation, with oxidative stress being implicated in its expression. During the search for compounds from natural sources with potential as therapeutic agents for allergic diseases via IL-33 signal modulation, we discovered significant IL-33 inhibitory activity in the methanol extract of Canavalia gladiata (sword bean) pods. Through chromatographic separation and liquid chromatography-mass spectrometry, we isolated 11 compounds (1-11) from the methanol extract. Furthermore, we assessed the inhibitory effects of these substances on IL-33/ST2 signaling in processes related to inflammatory and autoimmune diseases using an enzyme-linked immunosorbent assay. Among them, compounds 7, 10, and 11 exhibited substantial IL-33 inhibitory efficacy, with values reaching 78%, 86%, and 79% at 100 µM, respectively. Remarkably, compounds 7, 10, and 11 demonstrated significant and dose-dependent inhibition of IL-33 signaling at concentrations of 10, 50, and 100 µM. Computational molecular docking and dynamic simulations further elucidated the underlying mechanisms. These findings have promising pharmacological implications for allergy prevention and treatment associated with flavonoid glycosides derived from C. gladiata.

FFA4 has gained interest in recent years since its deorphanization in 2005 and the characterization of the Free Fatty Acids receptors family for their therapeutic potential in metabolic disorders. The expression of FFA4 (also known as GPR120) in numerous organs throughout the human body makes this receptor a highly potent target, particularly in fat sensing and diet preference. This offers an attractive approach to tackle obesity and related metabolic diseases. Recent cryo-EM structures of the receptor have provided valuable information for a potential active state although the previous studies of FFA4 presented diverging information. We performed molecular docking and molecular dynamics simulations of four agonist ligands, TUG-891, Linoleic acid, α-Linolenic acid, and Oleic acid, based on a homology model. Our simulations, which accumulated a total of 2 μs of simulation, highlighted two binding hotspots at Arg992.64 and Lys293 (ECL3). The results indicate that the residues are located in separate areas of the binding pocket and interact with various types of ligands, implying different potential active states of FFA4 and a highly adaptable binding intra-receptor pocket. This article proposes additional structural characteristics and mechanisms for agonist binding that complement the experimental structures.

Metallo-β-lactamases (MβLs) hydrolyze and inactivate β-lactam antibiotics, are a pivotal mechanism conferring resistance against bacterial infections. SMB-1, a novel B3 subclass of MβLs from Serratia marcescens could deactivate almost all β-lactam antibiotics including ampicillin (AMP), which has posed a serious threat to public health. To illuminate the mechanism of recognition and interaction between SMB-1 and AMP, various fluorescence spectroscopy techniques and molecular dynamics simulation were employed. The results of quenching spectroscopy unraveled that AMP could make SMB-1 fluorescence quenching that mechanism was the static quenching; the synchronous and three-dimensional fluorescence spectra validated that the microenvironment and conformation of SMB-1 were altered after interaction with AMP. The molecular dynamics results demonstrated that the whole AMP enters the binding pocket of SMB-1, even though with a relatively bulky R1 side chain. Loop1 and loop2 in SMB-1 undergo significant fluctuations, and α2 (71-73) and local α5 (186-188) were turned into random coils, promoting zinc ion exposure consistent with circular dichroism spectroscopy results. The binding between them was driven by a combination of enthalpy and entropy changes, which was dominated by electrostatic force in agreement with the fluorescence observations. The present study brings structural insights and solid foundations for the design of new substrates for β-lactamases and the development of effective antibiotics that are resistant to superbugs.

BACKGROUND: Mycotoxin contamination of food has been gaining increasing attention. Hidden mycotoxins that interact with biological macromolecules in food could make the detection of mycotoxins less accurate, potentially leading to the underestimation of the total exposure risk. Interactions of the mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) with high-molecular glutenin were explored in this study.
RESULTS: The recovery rates of AOH and AME (1, 2, and 10 μg kg-1) in three types of grains (rice, corn, and wheat) were relatively low. Molecular dynamics (MD) simulations indicated that AOH and AME bound to glutenin spontaneously. Hydrogen bonds and π-π stacking were the primary interaction forces at the binding sites. Alternariol with one additional hydroxyl group exhibited stronger binding affinity to glutenin than AME when analyzing average local ionization energy. The average interaction energy between AOH and glutenin was -80.68 KJ mol-1, whereas that of AME was -67.11 KJ mol-1.
CONCLUSIONS: This study revealed the mechanisms of the interactions between AOH (or AME) and high-molecular glutenin using MD and molecular docking. This could be useful in the development of effective methods to detect pollution levels. These results could also play an important role in the evaluation of the toxicological properties of bound altertoxins. © 2024 Society of Chemical Industry.

To address the ongoing challenges posed by the SARS-CoV-2 and potentially stronger viruses in the future, the development of effective methods to fabricate patterned graphene (PG) and other precisely functional products has become a new research frontier. Herein, we modeled the \"checkerboard\" graphene (CG) and stripped graphene (SG) as representatives of PG, and studied their interaction mechanism with the target protein (Mpro) by molecular dynamics simulation. The calculation results on the binding strength and the root mean square deviation values of the active pocket revealed that PG is an effective platform for adsorption, immobilization, and destruction of Mpro. Specifically, CG is found to promote disruption of the active pocket for Mpro, but the presence of \"checkerboard\" oxidized regions inhibits the adsorption of Mpro. Meanwhile, the SG can effectively confine Mpro within the non-oxidized strips and enhances their binding strength, but doesn\'t play well on disrupting the active pocket. Our work not only elucidates the biological effects of PGs, but also provides guidance for their targeted and precise utilization in combating the SARS-CoV-2.

In this work, the hierarchical topology ring (HTR+) algorithm, an extension of the HTR algorithm, was developed for identifying gas hydrate types, cage structures, and grain boundaries (GBs) within polycrystalline structures. Utilizing molecular dynamics trajectories of polycrystalline hydrates, the accuracy of the HTR+ algorithm is validated in identifying sI, sII and sH hydrate types, hydrate grains, and GBs in multi-hydrate polycrystals, as well as clathrate cages at GBs. Additionally, during the hydrate nucleation and growth processes, clathrate cages, hydrate type, hydrate grains and ice structures are accurately recognized. Significantly, this algorithm demonstrates high efficiency, particularly for large hydrate systems. HTR+ algorithm emerges a powerful tool for identifying micro/mesoscopic structures of gas hydrates, enabling an in-depth understanding of the formation mechanisms and properties of gas hydrates.