Search Results (2,389)

We present a computational study that precedes the potential interactions between SARS-CoV-2 helicase (NSP13) and selected host proteins implicated in chaperone-assisted folding and polyamine metabolism. Using structure-based modelling and protein–protein docking (BioLuminate v4.6), followed by all-atom molecular dynamics (MD) simulations (GROMACS v2018.6), and comparative MM-GBSA scoring (HawkDock v2), we evaluated the stability and interface properties of NSP13 complexes with cytosolic heat shock proteins; heat shock protein 40 (HSP40), heat shock protein 70 (HSP70), heat shock protein 90 (HSP90) and the polyamine biosynthesis enzyme ornithine decarboxylase (ODC). Docking, MD, and interface analyses indicate distinct complex behaviours: HSP70-NSP13 complexes sampled compact conformations, HSP90-NSP13 ensembles displayed greater conformational heterogeneity but more favourable comparative MM-GBSA estimates, and ODC-NSP13 interfaces were comparatively well packed. Per-residue contact mapping identified a small set of recurrent NSP13 residues, Lys22 and Asn51, as putative interaction hotspots. The reported findings herein generate testable hypotheses about NSP13 recruitment of host chaperones and modulation of polyamine metabolism that may inform downstream experimental studies. Full article

The zoonotic potential of bat coronaviruses, especially HKU5, is a significant issue because of their capacity to utilize human angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry. This study offers structural insights into the binding kinetics of HKU5 (Bat Merbecovirus HKU5) receptor-binding domain (RBD) spike protein with human ACE2 through a multiscale computational method. This study employed structural modeling, 300-nanosecond (ns) molecular dynamics (MD) simulations, alanine-scanning mutagenesis, and computational peptide design to investigate ACE2 recognition by the HKU5 RBD and its interactions with peptides. The root mean square deviation (RMSD) investigation of HKU5–ACE2 complexes indicated that HKU5 exhibited greater flexibility than SARS-CoV-2, with RMSD values reaching a maximum of 1.2 nm. Free energy analysis, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), indicated a more robust binding affinity of HKU5 to ACE2 (ΔG_Total = −21.61 kcal/mol) in contrast to SARS-CoV-2 (ΔG_Total = −5.82 kcal/mol), implying that HKU5 binding with ACE2 had higher efficiency. Additionally, a peptide was designed from the ACE2 interface, resulting in the development of 380 single-site mutants by mutational alterations. The four most promising mutant peptides were selected for 300-nanosecond (ns) MD simulations, subsequently undergoing quantum chemical calculations (DFT) to evaluate their electronic characteristics. MM/GBSA of −37.83 kcal/mol indicated that mutant-1 exhibits the most favorable binding with HKU5, hence potentially inhibiting ACE2 interaction. Mutant-1 formed hydrogen bonds involving Glu74, Ser202, Ser204, and Asn152 residues of HKU5. Finally, QM/MM calculations on the peptide–HKU5 complexes showed the most favorable ΔE_interaction of −170.47 (Hartree) for mutant-1 peptide. These findings offer a thorough comprehension of receptor-binding dynamics and are crucial for evaluating the zoonotic risk associated with HKU5-CoV and guiding the design of receptor-targeted antiviral treatments. Full article

Background: Due to chronic venous insufficiency, venous leg ulcers (VLUs) develop as chronic wounds characterized by impaired healing, persistent inflammation, and endothelial dysfunction. Nitrosative stress, mitochondrial damage, and tissue apoptosis caused by excess nitric oxide (NO) produced by iNOS in macrophages and fibroblasts are contributing factors in the chronic wound environment; therefore, pharmacological modulation of iNOS presents an attractive mechanistic target in chronic wound pathophysiology. Methods: Herein, we present the use of a structure-based computational strategy to assess the inhibition of tavaborole, a boron-based antifungal agent, against iNOS using human iNOS crystal structure (PDB ID: iNOS) by molecular docking using AutoDock 4.2, 500 ns simulation of molecular dynamics (MD), with equilibration within ~50 ns and analyses over full trajectory and binding free energy calculations through the MM-PBSA approach. Results: Docking studies showed favorable binding of tavaborole (–6.1 kcal/mol) in the catalytic domain, which stabilizes contacts with several key residues (CYS200, PRO350, PHE369, GLY371, TRP372, TYR373, and GLU377). MD trajectories for 1 ns showed stable structural configurations with negligible deviations (RMSD ≈ 0.44 ± 0.10 nm) and hydrogen bonding, and MM-PBSA analysis confirmed energetically favorable complex formation (ΔG_binding ≈ 18.38 ± 63.24 kJ/mol) similar to the control systems (L-arginine and 1400W). Conclusions: Taken together, these computational findings indicate that tavaborole can stably occupy the iNOS active site and interact with key catalytic residues, providing a mechanistic basis for further in vitro and ex vivo validation of its potential as an iNOS inhibitor to reduce nitrosative stress and restore endothelial homeostasis in venous leg ulcers, rather than direct therapeutic proof. Full article

Neonicotinoids are synthetic nicotine-like compounds extensively used globally as insecticides for agricultural and urban purposes. Neonicotinoid-contaminated produce is a major public health concern worldwide. Limited epidemiological studies have shown an association of neonicotinoid exposure with abnormal semen analysis. This study aimed to elucidate the potential disruption of the androgen receptor (AR) by eight common neonicotinoids, including imidacloprid (IMI), acetamiprid, clothianidin, thiamethoxam, dinotefuran, thiacloprid (THI), nitenpyram, and nithiazine using docking and molecular dynamics (MD) simulation. The results showed good binding strength of all compounds (except THI) with AR, as indicated by high binding energy, high binding affinity, and number of bonding interactions. The results of MD simulation supported the conformational stability and structural dynamic behavior of the AR-IMI (receptor-neonicotinoid) complex upon binding. This was indicated by root mean square deviation showing stability of the complex; the root mean square fluctuation showing minimized residual fluctuations upon binding; the radius of gyration showing greater compactness of the protein structure; the solvent-accessible surface area showing no changes upon binding; and the Gibbs funnel energy of the landscape showing a stable conformation state with minimum energy and slight change in size and position of the sampled energy basin of the AR, with a stable equilibrium. Taken together, the structural dynamics results showed that neonicotinoids are bound stably in the same ligand-binding domain of the AR as the native ligand testosterone. This may perturb the natural binding of testosterone with the AR and potentially disrupt downstream signaling and biological pathways, leading to male reproductive dysfunction. Full article

Vascular endothelial growth factor 165 (VEGF₁₆₅) stands out as a pivotal isoform of the VEGF-A protein and is critically involved in various angiogenesis-related diseases. Consequently, it has emerged as a promising target for diagnosing and treating such conditions. Structurally, VEGF₁₆₅ forms a homodimer, and each of its constituting monomers comprises a receptor-binding domain (RBD) and a heparin-binding domain (HBD). These two domains are linked by a flexible linker, and thus the overall structure of VEGF₁₆₅ remains incompletely understood. Aptamers are known as potent drugs that interact with VEGF₁₆₅, and dimeric aptamers that can simultaneously interact with two distant domains are frequently adopted to improve the potency. However, designing such aptamer dimers faces challenges in regard to determining the appropriate length of the linker connecting the two aptamer fragments. To gain insight into this distance information, we here employ biased molecular dynamics (MD) simulations with the umbrella sampling method, with the distance between the two HBDs serving as a reaction coordinate. Our simulations reveal an overall preference for compact conformations with HBD-HBD distances below 3 nm, with the minimum of the potential of mean force located at 1.1 nm. We find that VEGF₁₆₅ with the optimal HBD-HBD distance forms hydrogen bonds with its receptor VEGFR-2 that well match experimentally known key hydrogen bonds. We then try to computationally design aptamer homodimers consisting of two del5-1 aptamers connected by various linker lengths to target VEGF₁₆₅. Collectively, our findings may provide quantitative guidelines for rationally designing high-affinity aptamers for targeting VEGF₁₆₅. Full article

Cholinergic dysfunction is a hallmark of Alzheimer’s disease (AD), driven by elevated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity that depletes acetylcholine and contributes to amyloid pathology. Current AD treatments face major challenges, including poor brain penetration, short effect duration and safety concerns, highlighting the need for compounds suitable for preventive or earlier-stage intervention. This study investigated marine phytohormones as modulators of cholinergic imbalance, using an integrative strategy encompassing enzymatic assays, QSAR and DFT calculations, molecular docking, molecular dynamics (MD) simulations, and ADMET profiling. Among them, isopentenyl adenine (IPA) and abscisic acid (ABA) showed inhibitory activity against cholinesterases. IPA inhibited both AChE and BChE through distinct mechanisms with noncompetitive inhibition of AChE and competitive inhibition of BChE, while ABA showed selective noncompetitive inhibition of AChE. DFT-based analysis revealed distinct electronic properties supporting differential reactivity. Moreover, IPA interacted with both catalytic and peripheral residues in AChE, and aligned with BChE’s active site, while ABA was bound more peripherally. MD simulations confirmed complex-specific conformational stability based on RMSD, RMSF, Rg, and hydrogen bonding analysis. Both compounds showed low off-target potential against serine proteases and favorable predicted ADMET profiles. These results support the potential of marine phytohormones as preventive modulators of cholinergic dysfunction in AD. Full article

Background: Aggregatibacter actinomycetemcomitans is a Gram-negative, facultative anaerobic, immobile oral bacterium responsible for the secretion of virulence factors, namely leukotoxin (LtxA), a large exotoxin of the RTX family that enables the bacterium to evade the immune system by destroying leukocytes, resulting in aggressive periodontitis (AP) leading to tooth loss. Methods: This study aimed to screen 106 molecules derived from Moroccan propolis in order to identify potential inhibitors of the active sites of LtxA based on molecular docking, ADMET property evaluation, and molecular dynamics (MD) simulation. Results: Epigallocatechin gallate (EGCg), used as a reference compound, showed binding energies of −6.9 kcal/mol, −6.1 kcal/mol, −6.5 kcal/mol, and −5.9 kcal/mol with the four active sites P1, P2, P3, and P4, respectively. By establishing conventional hydrogen bonds, pi-alkyl bonds, and non-covalent pi–pi bonds. Chrysin and luteolin showed favorable binding affinities with the four active sites, named as follows: P1–P4 (P1–chrysin = −7.5 kcal/mol; P2–chrysin = −7.9 kcal/mol; P3–chrysin = −8.1 kcal/mol; P4–chrysin = −6.9 kcal/mol; P1–luteolin = −7.3 kcal/mol; P2–luteolin = −7.6 kcal/mol; P3–luteolin = −8.1 kcal/mol; P4–luteolin = −7.3 kcal/mol). The binding affinity of these two propolis derivatives was stabilized by pi−sigma bonds, pi−alkyl bonds, conventional hydrogen bonds, pi-cation interactions, non-covalent pi–pi bonds, and carbon–hydrogen bonds. According to free energy calculations performed with Prime MM-GBSA, the complexes formed by chrysin demonstrated the most stable interactions due to Van der Waals and lipophilic forces. Luteolin formed significant interactions, but slightly weaker than those of chrysin. These results reveal the inhibitory potential of chrysin and luteolin with protein active sites. MD simulations corroborated the excellent stability of complexes formed by chrysin, as indicated by low RMSD values, suggesting favorable dynamic behavior. Conclusions: These results highlight the potential of chrysin as a versatile inhibitor capable of interacting with the four active sites. These findings are a strong foundation for further experimental confirmations. Full article

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced skin damage. The agouti signaling protein (ASIP) antagonizes the melanocortin-1 receptor (MC1R), hinders melanocyte signaling, and shifts pigmentation toward pheomelanin, promoting UV vulnerability. In this study, we aim to discover compounds that inhibit ASIP–MC1R interaction and effectively preserve eumelanogenic signaling. Methods: The ASIP–MC1R interface-based pharmacophore model from ASIP is implicated in MC1R receptor protein engagement. We performed virtual screening with a validated pharmacophore model for ~4000 compounds curated from ZINCPharmer and applied drug-likeness filters, viz. ADMET and toxicity profiling tests. Further, the screened candidates were targeted for docking to the ASIP C-terminal domain corresponding to the MC1R-binding moiety. Top compounds underwent a 100-nanosecond (ns) run of molecular dynamics (MD) simulations to assess complex stability and persistence of key contacted residues. Results: Sequential triage, including pharmacophore, ADME–toxicity (ADMET), and docking/ΔG, yielded a focused group of candidates against ASIP antagonists with a favorable fit value. The MD run for 100 ns supported pose stability at the targeted pocket. Based on these predictions and analyses, compound ZINC14539068 was screened as a new potent inhibitor of ASIP to preserve α-MSH-mediated signaling of MC1R. Conclusions: Our in silico pipeline identifies ZINC14539068 as a potent inhibitor of ASIP at its C-terminal interface. This compound is predicted to disrupt ASIP–MC1R binding, thereby maintaining eumelanin-biased signaling. These findings motivate experimental validation in melanocytic models and in vivo studies to confirm pathway modulation and anti-melanoma potential. Full article

This study utilized a dynamic cross-linking algorithm to formulate a chemical cross-linked hydrogel model of poly(N-isopropylacrylamide) (PNIPAM) with N, N’-methylenebisacrylamide (BIS). Molecular dynamics (MD) simulations were conducted to investigate the temperature sensitivity and ibuprofen release mechanism of this hydrogel under varying cross-linking degrees and water contents. The low critical solution temperature (LCST) of the hydrogel was determined based on changes in solvent-accessible surface area (SASA) and hydrogen bond count. The LCST was found to be between 300 and 310 K. As the temperature increased, both SASA and hydrogen bond counts generally exhibited a gradual decrease. However, near the LCST, polymer chain collapse temporarily exposed the hydrophilic groups of the PNIPAM, forming hydrophilic regions that increased the contact area with water. This led to a transient increase in SASA (8% higher than that before 300 K) and hydrogen bond counts (6.25% higher than that at 290 K). Concurrently, Young’s modulus of the PNIPAM hydrogel was found to decrease with increasing water content (from 3.11 GPa to 2.59 GPa, representing a 16.7% decrease when water content increased from 0% to 50% for 80% cross-linking degree) and increase with rising cross-linking density (from 2.02 GPa to 2.94 GPa, representing a 45.5% increase when the cross-linking degree increased from 0% to 80% for 20% water content). These findings indicate that enhancing cross-linking density is an effective strategy for improving the hydrogel’s mechanical properties. A PNIPAM–ibuprofen delivery model was constructed and molecular dynamics (MD) simulations were conducted, revealing temperature dependence release behavior. Below the LCST, the PNIPAM hydrogel remains in a highly swollen state (PNIPAM single-chain radius of gyration, Rg = 0.64 nm at 290 K), with ibuprofen molecules adsorbed within the PNIPAM polymer chain network. Conversely, above the LCST, PNIPAM undergoes phase separation (Rg decreases to 0.56 nm at 320 K, representing a 12.5% decrease), resulting in volume contraction (cavity volume reduced by 35%) and disruption of the hydrogen bond network. This process results in the release of ibuprofen molecules, accompanied by an increase in their diffusion coefficient from 1.3817 × 10⁻⁹ (280 K) to 4.2847 × 10⁻⁹ m²/s (320 K). Concurrently, the interaction energy with PNIPAM experiences a decline, from −126.72 kcal/mol to −108.69 kcal/mol. The findings of this study provide insights into the optimization of the structural stability of ibuprofen delivery carriers. Full article

Nano-aluminum (nAl), characterized by its high combustion enthalpy and enhanced reactivity, serves as a critical component in advanced energetic materials like solid propellants and micro-ignition devices. However, the atomic-scale mechanisms governing its core–shell structure evolution, oxidation dynamics, and interfacial interactions remain elusive to experimental probes due to spatiotemporal limitations. Molecular dynamics (MD) simulations, particularly the synergistic use of a ReaxFF reactive force field (for large-scale systems) and ab initio MD (for electronic-level accuracy), have emerged as a powerful tool to overcome this barrier. This review systematically delineates the oxidation mechanisms and core–shell structure regulation of nAl, with a focus on the multi-scale simulation paradigm integrating DFT, AIMD, and ReaxFF MD that directly supports nAl research. It critically examines the pivotal role of MD simulations in guiding the surface modification of nAl, elucidating combustion mechanisms at the atomic level, and designing interfaces in energetic composite systems. By synthesizing recent advances (2022–2025), this study establishes a clear structure–property relationship between microscopic features and macroscopic performance of nAl. Furthermore, it identifies prevailing challenges, including simulations under multi-physics loading, multi-scale bridging, and quantitative experiment-simulation validation that specifically affect nAl-based energetic systems. Finally, future research directions are prospected, encompassing the development of machine learning-empowered force fields tailored for nAl systems, multi-scale and multi-field coupling simulation frameworks targeting nAl applications, and closed-loop experiment-simulation systems for nAl-based energetic materials. This review aims to provide fundamental insights and a technical framework for the rational design and engineering application of nAl-based energetic materials in fields such as aerospace propulsion. Full article

The widespread use of antibiotics, combined with pervasive exposure to diverse environmental media, has intensified the global challenge of antibiotic resistance. Accumulating evidence reveals that beyond direct antibiotic pressure, residual non-antibiotic chemicals—despite lacking intrinsic antibacterial activity—can significantly promote the enrichment and spread of antibiotic resistance genes (ARGs) in farmland soils through indirect mechanisms such as inducing oxidative stress, altering microbial community structure, and enhancing both vertical and horizontal gene transfer. To address this issue, the present study investigates the influence of representative non-antibiotic contaminants commonly detected in agricultural environments—including pesticides (e.g., Omethoate, imidacloprid, and atrazine), industrial pollutants (e.g., PCB138, BDE47, benzo [a] pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], and benzene), plastic-associated compounds (e.g., Polyethylene trimer, phthalates, and tributyl acetylcitrate), and ingredients from personal care products (e.g., triclosan and bisphenol A)—on ARG transmission dynamics. Leveraging bioinformatics resources such as the CARD database, PDB, AlphaFold, and molecular sequence analysis tools, we identified relevant small-molecule ligands and macromolecular receptors to construct a simulation system modeling ARG transfer pathways. Molecular docking and molecular dynamics (MD) simulations were then implemented, guided by a Plackett–Burman experimental design, to systematically evaluate the impact of individual and co-occurring pollutants. The resulting data were processed using advanced analytical tools, and MD trajectories were interpreted at the molecular level across three scenarios: an unperturbed (blank) system, single-pollutant exposures, and dual-pollutant combinations. By integrating computational simulations with machine learning approaches, this work uncovers the “co-selection” effect exerted by non-antibiotic chemical residues in shaping the environmental resistome, thereby providing a mechanistic and scientific basis for comprehensive risk assessment of agricultural non-point source pollution and the development of effective soil health management and antimicrobial resistance containment strategies. Full article

Based on static scale inhibition experiments and molecular dynamics (MD) simulations, this study investigated the influence of concentration and temperature on the scale inhibition performance and adsorption behavior of the hydroxyphosphonic acid-based XCN scale inhibitor on calcite (104) surfaces. Experimental results demonstrate that XCN exhibits excellent inhibition efficiency against CaCO₃ scale, achieving 91.26% at 30 ppm and 60 °C. Further increasing the concentration to 35 ppm improves the inhibition rate by only 0.52%, a marginal gain attributable to the threshold effect. Performance improves with decreasing temperature, increasing from 91.26% at 60 °C to 96.92% at 30 °C. MD simulations reveal that the adsorption energy between XCN and calcite peaks at a specific molecular count (9 molecules), indicating optimal surface coverage. Radial distribution function analyses confirm chemisorption via Ca-O and Ca-H interactions within 1–3.5 Å, inducing lattice distortion that inhibits crystal growth. However, increasing temperature weakens adsorption and promotes molecular desorption, reducing inhibition efficiency. These findings provide molecular-level insights into the threshold and thermal behaviors of phosphonic acid scale inhibitors, supporting the optimized application of XCN in oilfield operations. Full article

Coordination polymers (CPs) are garnering attention in the field of medicine day by day. The goal is to develop a CP with biosafe and environment-friendly characteristics. Herein, we report two such novel 3D coordination polymers of zinc-inosine-5′-monophosphate (Zn-IMP) and bpe/azpy (as linkers) which were engineered as metal–organic frameworks that can be used as drug carriers for hydroxyurea (HU). We employed SCXRD, PXRD, solid-state CD, FTIR and TGA for crystal structure characterizations; the results achieved 3D coordination polymers which contain a P2₁ space group with chiral distorted tetrahedral geometry. Solution phase studies like UV–vis and CD were carried out to understand mechanistic pathways for interaction and chirality, respectively. We have also performed computational studies to evaluate the drug delivery capacity of both 3D CPs. Molecular docking and multi-pH molecular dynamics (MD) quantify that HU binds more strongly with CP−1 (ΔG =−10.87 ± 0.12) as compared to CP−2 (ΔG = −7.59 ± 0.26 kcal·mol⁻¹), at normal and basic pH. MD simulation analysis indicated that a more compact and rigid cavity is observed by CP−1 as compared to CP−2 at physiological pH. Across acidic pH, for CP−1 the ligand RMSD increases markedly and U becomes slightly less negative, which indicated partial loss of contacts, thus releasing drugs in a tumor-like environment more easily. These result showed that CP−1 offers stronger binding, higher structural stability and a more pronounced pH-responsive release profile than CP−2, making CP-1 more promising candidate for targeted HU drug delivery, while CP−2 may serve as a weaker-binding, faster-release complement. Full article

The influence of 5-Methyl-1H-benzotriazole (MHBTZ) on the corrosion of pure iron (Fe) and aluminum (Al) in 1 M HCl was investigated in this study. The experimental and theoretical aspects of MHBTZ adsorption onto pure iron (Fe) and aluminum metal (Al) surfaces, as well as the stability of adsorbed layers based on the metal type, were also studied. Different electrochemical measurements were performed to explore the corrosion rates and inhibition efficiencies on the Fe and Al surfaces at 298 K. Optical profilometry was used to obtain the 3D surface topography of Fe and Al metals after immersion with and without the MHBTZ molecule. The results showed that MHBTZ exhibited excellent inhibition properties for both metals. Electrochemical impedance spectroscopy (EIS) achieved inhibition efficiencies of 98.1% and 98.5% for Fe and Al, respectively, at a concentration of 2500 ppm. Potentiodynamic polarization (PDP) indicated that MHBTZ acted as a mixed-type inhibitor. Density functional theory (DFT) analysis and molecular dynamics (MD) simulations were used to explore the relationship between the molecular structure of MHBTZ and its inhibition efficiency at the atomic level. Full article

Toll-like receptor 7 (TLR7) and Stimulator of Interferon Genes (STING) ligands possess a series of immunomodulatory effects such as anti-infection, anti-tumor, and autoimmune-disease-alleviating effects. In this study, porcine TLR7 (pTLR7) and porcine STING (pSTING) were selected as targets, and molecular docking and virtual screening methods were used for screening of dual-target livestock immunomodulators. Finally, two compounds were screened with molecular docking scores higher than the positive control compounds. They have good binding ability with pTLR7 and pSTING proteins, as well as satisfactory predictive safety and pharmacokinetic properties. Molecular dynamics (MD) simulation results also indicated that the above ligands can form stable complexes with two target proteins. The average binding free energies of compound 2 with pTLR7 and pSTING were −28.65 kcal/mol and −30.12 kcal/mol, respectively, and of compound 7 with pTLR7 and pSTING were −35.93 kcal/mol and −31.70 kcal/mol, respectively, which were comparable to that of positive control ligands. The similarity of target proteins between pigs, humans, and mice, as well as the interactions between ligands and TLR7 and STING in different species, were analyzed. And analysis of predicted structure–activity relationship (SAR) was conducted. Briefly, compound 2 and compound 7 were predicted to form stable complexes with pTLR7 and pSTING, with satisfactory predicted physicochemical properties and pharmacokinetic characteristics, and represented candidates for experimental validation. This study supplies a research basis for the development, design, and structural modification of immune enhancers for animals. Full article