Search Results (279)

During the process of flexible aerial refueling, the flexible structure of the hose drogue assembly is affected by internal and external interference, such as docking maneuvering, deformation of the hose, attitude changes, and body vibrations, causing the hose to swing and the whipping phenomenon, which greatly limits the success rate and safety of aerial refueling operations. Based on a 2.4 m transonic wind tunnel, high-speed wind tunnel test technology of a flexible aerial refueling hose–drogue system was established to carry out experimental research on the coupling characteristics of aerodynamics and multi-body dynamics. Based on the aid of Videogrammetry Model Deformation (VMD), high-speed photography, dynamic balance, and other wind tunnel test technologies, the dynamic characteristics of the hose–drogue system in a high-speed airflow and during the approach of the receiver are obtained. Adopting flexible multi-body dynamics, a dynamic system of the tanker, hose, drogue, and receiver is modeled. The cable/beam model is based on an arbitrary Lagrange–Euler method, and the absolute node coordinate method is used to describe the deformation, movement, and length variation in the hose during both winding and unwinding. The aerodynamic forces of the tanker, receiver, hose, and drogue are modeled, reflecting the coupling influence of movement of the tanker and receiver, the deformation of the hose and drogue, and the aerodynamic forces on each other. The tests show that during the approach of the receiver (distance from 1000 mm to 20 mm), the sinking amount of the drogue increases by 31 mm; due to the offset of the receiver probe, the drogue moves sideways from the symmetric plane of the receiver. Meanwhile, the oscillation magnitude of the drogue increases (from 33 to 48 and from 48 to 80 in spanwise and longitudinal directions, respectively). The simulation results show that the shear force induced by the oscillation of the hose and the propagation velocity of both the longitudinal and shear waves are affected by the hose stiffness and Mach number. The results presented in this work can be of great reference to further increase the safety of aerial refueling. Full article

The recent global coronavirus pandemic highlighted the ever-present threat of respiratory virus outbreaks and the consequent need for ongoing research into antiviral therapy. To this end, structural analogues of the guanidinium-based drug camostat mesylate have been synthesised to probe their potential inhibition of Transmembrane Serine Protease 2 (TMPRSS2), a human protease that is essential for infection by many respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Our in vitro fluorescence-based protease assays and supporting computational docking studies suggest that C-terminal camostat analogues retain TMPRSS2 inhibition potencies (IC₅₀ = 1–3 nM, BE = −6.6 to −7.0 kcal/mol) that match or exceed that of the parent drug. Analogues 1c and 1d emerge as lead candidates in this regard, thereby validating the rationale behind C-terminal structural modifications and highlighting these derivatives as promising scaffolds for the future development of targeted antiviral therapeutics. Replacement of camostat’s ester functionality with peptide linkages largely preserves non-covalent binding but disrupts in vitro protease inhibition, findings consistent with the parent drug’s known role as an acylating suicide inhibitor. Docking studies confirm that the replacement of aromatic residues with flexible, equivalent-length alkyl chains is detrimental to drug binding. These function and binding data offer new directions for the synthesis of further analogues of camostat and of other guanidinium-based protease inhibitors that have yet to be refined via structure–activity relationship studies. Further investigation will support tailoring this class of drugs for repurposing in antiviral therapy. Full article

L-asparaginase (L-ASNase) is a key industrial enzyme significant for cancer therapy and the food industry for reducing dietary acrylamide. The hyperthermophilic L-ASNase from Thermococcus sibiricus (TsAI) was previously shown to exhibit high activity and thermostability and is promising for biotechnology. To gain insights into structure-functional relationships of TsAI, determination of the substrate specificity, kinetic parameters, structural characterization, and molecular docking were performed. TsAI characteristics were compared with the TsAI^D54G/T56Q mutant, which exhibited increased activity after a double mutation in the substrate-binding region. TsAI and TsAI^D54G/T56Q were found to display high activity towards D-asparagine—62% and 21% of L-asparaginase activity, respectively—and low L-glutaminase coactivity of ~5%. Restoring the mesophilic-like triad GSQ in the mutant resulted in a two-fold increase in activity towards L-asparagine compared with TsAI. Crystal structures of TsAI forms solved at 1.9 Å resolution revealed that double mesophilic-like mutation increased the flexibility of the loop M51-L57, located in close proximity to the active site. Structural superposition and mutational analysis indicate that mobility of this loop is essential for the activity of thermo-ASNases. Molecular docking, without taking into account the temperature factor, showed that, in contrast to L-asparagine interaction, D-asparagine orientation in the TsAI and TsAI^D54G/T56Q active sites is similar and not optimal for catalysis. Under real conditions, high temperatures can induce structural changes that reduce L-ASNase discrimination towards D-asparagine. Overall, the obtained structural and biochemical data provide a basis for a more detailed understanding of thermo-ASNase functioning and possibilities to engineer improved variants for future biotechnological application. Full article

Panax ginseng has been used as a traditional Oriental medicinal herb. This research investigates the potential of ginsenosides, bioactive phyto compounds derived from ginseng, as ligands of the solute carrier (SLC) family, including SLC3A2, SLC7A6, SLC7A11, SLC7A5, SLC7A8, SLC43A1, LCN2, SLC7A9, SLC7A7, and SLC7A10 proteins—which are overexpressed in various cancers and linked to metastasis. Using molecular docking (MD), ginsenosides (Km, Ro, compound K (CK), Rk1, and Ra1) with high binding affinities to SLC3A2 were identified, exhibiting binding energies of −9.3, −9.1, −8.7, −8.0, and −7.7 kcal/mol, respectively. Further molecular dynamics simulations (MDSs) conducted using GROMACS revealed improved stability, flexibility, and dynamic behavior of the selected ginsenosides, predicting their potential as natural ligands to bind with SLC3A2. Though this computational prediction underscores these ginsenosides as promising candidates as natural ligands to bind and interact with SLC family proteins during anti-cancer therapies, further in vitro and in vivo studies are needed to validate these interactions and anti-cancer effects. Full article

Background/Objective: Avapritinib is an orally bioavailable tyrosine kinase inhibitor and was approved by the FDA in 2020 for gastrointestinal stromal tumor treatments. Although avapritinib is known to be chiral, its stereochemistry was initially established randomly. This study aims to develop a definitive method for determining avapritinib’s absolute configuration and propose a universal methodology for stereochemical characterization of flexible chiral drugs. Methods: The absolute configuration of avapritinib was determined through an integrated approach combining chiral resolution, chiroptical spectroscopy and synthetic validation. Enantiomeric separation was achieved via chiral liquid chromatography, followed by comprehensive chiroptical characterization including electronic circular dichroism (ECD), specific optical rotation and optical rotatory dispersion. Conformational analysis and density functional theory (DFT) calculations correlated experimental spectra with theoretical predictions, facilitating definitive configurational assignment. The stereochemical determination were further verified through ECD derivatization and chemical synthesis. Finally, the enantiomers’ kinase inhibition profiles against c-KIT D816V were quantitatively assessed. Results: Two enantiomers of avapritinib were resolved via chiral HPLC and a Chiralpak IG column. Through combined experimental ECD spectra and time-dependent DFT calculations employing the core extraction method, the levo-isomer was unambiguously determined as S configuration. This stereochemical assignment was confirmed by p-cyanobenzaldehyde derivatization and de novo synthesis. Biological evaluation revealed (S)-(−)-avapritinib exhibited superior c-KIT D816V inhibitory activity compared to its (R)-(+)-counterpart, a finding corroborated by molecular docking studies elucidating their differential target interactions. Conclusions: This study advances avapritinib stereochemical understanding and establishes a definitive protocol for its absolute configuration assignment, serving as a paradigm for flexible chiral drug characterization. Full article

Clusterin is one of the many known proteins implicated in cancer chemoresistance, which hinders the effectiveness of chemotherapy. This study aimed to design novel inhibitors targeting clusterin using fragment-based drug discovery (FBDD). This approach aims to develop new medicines by identifying small, simple molecules known as “fragments” that can bind to a specific target, such as a disease-causing protein. In this study, a primary ligand-binding site and an allosteric site on the clusterin molecule were identified through hotspot analysis. We screened commercially available fragment libraries for anti-cancer activity and applied the “rule of three” to ensure drug-like properties. The highest-affinity fragment underwent “fragment-growing” to develop potential drug candidates. After docking and toxicity screening, 194 candidate drugs were identified. Quantitative structure-activity relationship (QSAR) analysis revealed that the chemical size and complexity of the fragments significantly contributed to their binding affinity. Pharmacokinetic analyses of candidate drugs from FBDD followed by molecular dynamics simulation of the top 1 final candidate drug precursor demonstrated comparatively better affinity (average = −34.01 kcal/mol) than the reference compound (average = −6.15 kcal/mol) and significant ligand flexibility. This study offers a potential strategy to identify fragments or molecules that may serve as drugs against clusterin-related chemoresistance. Full article

The maritime shipping sector is a major contributor to greenhouse gas emissions, particularly in coastal regions. In response, the adoption of electric ferries powered by renewable energy and supported by battery storage technologies has emerged as a viable decarbonization pathway. This study investigates the operational impacts of coordinated electric ferry charging on a medium-voltage distribution network at Gladstone Marina, Queensland, Australia. Using DIgSILENT PowerFactory integrated with MATLAB Simulink and a Python-based control system, four proposed ferry terminals equipped with BESSs (Battery Energy Storage Systems) are simulated. A dynamic model of BESS operation is optimized using a balanced hybrid metaheuristic algorithm combining GA-PSO-BFO (Genetic Algorithm-Particle Swarm Optimization-Bacterial Foraging Optimization). Simulations under 50% and 80% transformer loading conditions assess the effects of charge-only versus charge–discharge strategies. Results indicate that coordinated charge–discharge control improves voltage stability by 1.0–1.5%, reduces transformer loading by 3–4%, and decreases feeder line loading by 2.5–3.5%. Conversely, charge-only coordination offers negligible benefits. Further, quasi-dynamic analyses validate the system’s enhanced stability under coordinated energy management. These findings highlight the potential of docked electric ferries, operating under intelligent control, to act as distributed energy reserves that enhance grid flexibility and operational efficiency. Full article

A series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, 6c1, exhibited strong BChE inhibition (IC₅₀ = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure–activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development. Full article

Superoxide dismutase 1 (SOD1) is a crucial enzyme that protects cells from oxidative damage by converting superoxide radicals into H₂O₂ and O₂. This detoxification process, essential for cellular homeostasis, relies on a precisely orchestrated catalytic mechanism involving the copper cation, while the zinc cation contributes to the structural integrity of the enzyme. This study presents the 2.3 Å crystal structure of human SOD1 (PDB ID: 9IYK), revealing an assembly of six homodimers and twelve distinct active sites. The water molecules form a complex hydrogen-bonding network that drives proton transfer and sustains active site dynamics. Our structure also uncovers subtle conformational changes that highlight the intrinsic flexibility of SOD1, which is essential for its function. Additionally, we observe how these dynamic structural features may be linked to pathological mutations associated with amyotrophic lateral sclerosis (ALS). By advancing our understanding of hSOD1’s mechanistic intricacies and the influence of water coordination, this study offers valuable insights for developing therapeutic strategies targeting ALS. Our structure’s unique conformations and active site interactions illuminate new facets of hSOD1 function, underscoring the critical role of structural dynamics in enzyme catalysis. Moreover, we conducted a molecular docking analysis using SOD1 for potential radical scavengers and Abelson non-receptor tyrosine kinase (c-Abl, Abl1) inhibitors targeting misfolded SOD1 aggregation along with oxidative stress and apoptosis, respectively. The results showed that CHEMBL1075867, a free radical scavenger derivative, showed the most promising docking results and interactions at the binding site of hSOD1, highlighting its promising role for further studies against SOD1-mediated ALS. Full article

Glycosaminoglycans (GAGs) are key ligands for proteins involved in physiological and pathological processes. Specific GAG-binding patterns are rarely identified, with the heparin pentasaccharide as an Antithrombin-III ligand being the best characterized. Generating glycan-specific antibodies is difficult due to their size, pattern dispersion, and flexibility. Single-domain variable new antigen receptors (VNAR nanobodies) from nurse sharks are highly soluble, stable, and versatile. Their unique properties suggest advantages over conventional antibodies, particularly for challenging biotherapeutic targets. Here we have used VNAR semi-synthetic phage libraries to select high-affinity fondaparinux-binding VNARs that did not show cross-reactivity with other GAG species. Competition ELISA and surface plasmon resonance identified a single fondaparinux-selective VNAR clone. This VNAR exhibited an extraordinarily stable protein fold: the beta-strands are stabilized by a robust hydrophobic network, as revealed by heteronuclear NMR. Docking fondaparinux to the VNAR structure revealed a large contact surface area between the CDR3 loop of the antibody and the glycan. Fusing the VNAR with a human Fc domain resulted in a stable product with a high affinity for fondaparinux (Kd = 9.3 × 10⁻⁸ M) that could efficiently discriminate between fondaparinux and other glycosaminoglycans. This novel glycan-targeting screening technology represents a promising therapeutic strategy for addressing GAG-related diseases. Full article

Deep eutectic solvents (DESs) have shown promise as a medium for extracting polar volatile fatty acids (VFAs) and in situ esterification of the extracted molecules using lipases. This solvent enhanced biocatalysis process can potentially streamline VFA separation from fermentation broth by integrating conversion and extraction steps. Two commercial lipases from Aspergillus oryzae (AoL) and Candida rugosa (CrL) were evaluated in reaction systems containing hydrophilic or hydrophobic DESs using a newly optimized lipase assay. The optimal pH for both lipases was around 5.0, with a slight reduction in activity at pH 8.0 and a significant inhibition at pH 2.0. The impact of DES concentration on lipase activity varied depending on the specific DES–lipase pairs. Most hydrophilic DESs show good compatibility with the tested lipases. Specifically for choline chloride/ethylene glycol (1:2) and choline chloride/levulinic acid (1:2), taking into account the influence of pH, CrL activity increased with DES concentration. However, the hydrophobic DES thymol/2,6-dimethoxyphenol (1:2) demonstrated enhanced inhibitory effects on both lipases. Docking simulation helped explain the ligand–protein interactions but showed limited capability in predicting the compatibility of specific DES–lipase pairs due to its constraints in simulating flexible protein structures and the complex interactions between DES components and water. Full article

Molecular modelling is a vital tool in the discovery and characterisation of bioactive peptides, providing insights into their structural properties and interactions with biological targets. Many models predicting bioactive peptide function or structure rely on their intrinsic properties, including the influence of amino acid composition, sequence, and chain length, which impact stability, folding, aggregation, and target interaction. Homology modelling predicts peptide structures based on known templates. Peptide–protein interactions can be explored using molecular docking techniques, but there are challenges related to the inherent flexibility of peptides, which can be addressed by more computationally intensive approaches that consider their movement over time, called molecular dynamics (MD). Virtual screening of many peptides, usually against a single target, enables rapid identification of potential bioactive peptides from large libraries, typically using docking approaches. The integration of artificial intelligence (AI) has transformed peptide discovery by leveraging large amounts of data. AlphaFold is a general protein structure prediction tool based on deep learning that has greatly improved the predictions of peptide conformations and interactions, in addition to providing estimates of model accuracy at each residue which greatly guide interpretation. Peptide function and structure prediction are being further enhanced using Protein Language Models (PLMs), which are large deep-learning-derived statistical models that learn computer representations useful to identify fundamental patterns of proteins. Recent methodological developments are discussed in the context of canonical peptides, as well as those with modifications and cyclisations. In designing potential peptide therapeutics, the main outstanding challenge for these methods is the incorporation of diverse non-canonical amino acids and cyclisations. Full article

Drug intake, its absorption in the body, removal, and various side effects are factors considered when designing the drugs. Here, the in silico tools act as virtual shortcuts, assisting in the prediction of several important physicochemical properties like polar surface area (PSA), molecular weight, and molecular flexibility, etc., to evaluate probable drug leads as potential drug candidates. These tools also play a vital role in the prediction of the bioactivity score of probable drug leads against various human receptors. This paper presents a virtual combinatorial library of selected thiosemicarbazones (TSCs) and their metal complexes. Different properties like bioactivity score, physicochemical, distribution, absorption, excretion, metabolism, and toxicity (ADMET) parameters were assessed. By using ChemDraw Ultra 12.0, the structures of ligands and complexes were drawn and downloaded in PDB format. Physicochemical parameters were calculated using online softwares viz. Molinspiration and SwissADME, and ADMET properties were calculated using admetSAR (2.0). Molecular docking was performed using PyRx Python Prescription 0.8. with Janus Kinase and Transforming Growth Factor Beta (Tgf-β). Janus Kinase and Tgf-β are some cytokines involved in cell development, proliferation, and cell death. Three important TSCs, i.e., salicyldehyde thiosemicarbazone, acenaphthenequinone thiosemicarbazone, 2-chloronicotinic thiosemicarbazone, and their virtually designed complexes exhibited appreciable in silico results. Most ligands and complexes had good bioactivity values against all the biological targets. Full article

With the continuous development of modern robotics technology, in order to overcome the obstacles to the ability to complete tasks due to the fixed structure of the robot itself, to realize the reconfigurable purpose of the manipulator, it can be assembled into different degrees of freedom or configurations according to the needs of different tasks, which has the characteristics of a compact structure, high integrability, and low cost. The overall design scheme of a cable-free modular reconfigurable manipulator is proposed, and based on the target design parameters, the structural design of each module is completed, and the module library is constructed. Each module realizes rapid assembly or disassembly through a new type of docking mechanism module, which improves the flexibility and reliability of the manipulator. Meanwhile, a finite element analysis is carried out on the whole manipulator to optimize the structure that does not meet the strength and stiffness requirements. The wireless energy transmission module is integrated into the joint module to realize the cable-free design of the manipulator in the structure. The kinematic models of each module are established separately, providing a method to quickly construct the kinematics of different configurations of the manipulator, and the dexterity of the workspace is analyzed. Then, two methods, joint space planning and Cartesian space planning, are adopted to generate the corresponding motion paths and kinematic curves, which successfully verifies the reasonableness of the kinematics of the designed manipulator. Finally, combined with the results of the dynamics simulation, the corresponding dynamics curves of the end of each joint are generated to further verify the reliability of its design. It provides a new way of thinking for the research and development of highly intelligent and highly integrated manipulators. Full article

Background: Diosgenin, a powerful compound found in fenugreek and Dioscorea villosa, has diverse pharmacological effects. This study examines the anticancer potential of diosgenin nanoparticles (Dio-NPs) against DMBA-induced breast cancer in mice in combination with tamoxifen. Methods: In the current investigation, characterization of Dio-NPs was performed, including their size, shape, zeta potential, UV-vis, and FT-IR spectra. Dio-NPs (120 mg/kg) and tamoxifen (2 mg/kg) were given to mice with DMBA-induced breast cancer, either alone or in combination, over 4 weeks. We measured inflammatory and oxidative stress markers, as well as gene expressions related to apoptosis, using ELISA and qRT-PCR. Additionally, molecular docking studies were conducted to assess the binding affinity of diosgenin with specific proteins. Molecular dynamics simulations were conducted on CDK4, AKT, and CDK6 proteins with diosgenin using GROMACS. The systems were solved, neutralized, and equilibrated under NVT and NPT ensembles. Simulations ran for 100 ns, and trajectories were analyzed for RMSD, RMSF, RG, SASA, and hydrogen bonds. Results: The IC₅₀ of Dio-NPs against MCF-7 cells was 47.96 ± 1.48 µg/mL. Dio-NPs had a zeta potential of −21.8 ± 0.6 mV and a size of 56.85 ± 3.19 nm and were uniform and spherical. The LD₅₀ of Dio-NPs was 2400 mg/kg. DMBA exposure increased WBCs, inflammatory markers, oxidative stress, and gene expression of CDK2, CDK4, CDK6, and Akt, while reducing Hb%, RBCs, PLTs, GSH, superoxide dismutase, and catalase levels. Dio-NPs and tamoxifen, both alone and combined, significantly reduced these effects. The combination treatment was more effective than individual treatments. Histological analyses supported these findings. Molecular docking showed diosgenin had a stronger binding affinity with the target proteins compared to tamoxifen. The simulations revealed that diosgenin effectively binds to CDK4, AKT, and CDK6, maintaining their stability and structural integrity. CDK4, AKT, and CDK6 showed consistent RMSD, RG, and SASA values, with moderate flexibility and stable hydrogen bonding patterns, suggesting their potential as therapeutic targets. Conclusions: Combining diosgenin and tamoxifen effectively inhibits breast cancer progression in DMBA-treated mice. This is primarily due to the reduction in expression of CDK2, CDK4, CDK6, and Akt proteins, which enhances the sensitivity of resistant breast cancer cells to tamoxifen. Full article