Strong Binding Affinity Research Articles

The molecular binding sequence transformation of soil organic matter and biochar dissolved black carbon antagonizes the transport of 2,4,6-trichlorophenol

Dissolved organic matter (DOM) and dissolved black carbon (DBC) are significant environmental factors that influence the transport of organic pollutants. However, the mechanisms by which their molecular diversity affects pollutant transport remain unclear. This study elucidates the molecular binding sequence and adsorption sites through which DOM/DBC compounds antagonize the transport of 2,4,6-trichlorophenol (TCP) using column experiments and modelling. DBC exhibits a high TCP adsorption rate (kn = 5.32 × 10−22 mol1–n∙Ln–1∙min−1) and conditional stability constant (logK = 5.19–5.74), indicating a strong binding affinity and antagonistic effect on TCP. This is attributed to the high relative content of lipid/protein compounds in DBC (25.65 % and 30.28 %, respectively). Moreover, the small molecule lipid compounds showed stronger TCP adsorption energy (Ead = −0.0071 eV/−0.0093 eV) in DOM/DBC, combined with two-dimensional correlation spectroscopy model found that DOM/DBC antagonized TCP transport in the environment through binding sequences that transformed from lipid/protein small molecule compounds to lignin/tannin compounds. This study used a multifaceted approach to comprehensively assess the impact of DOM/DBC on TCP transport. It reveals that the molecular diversity of DOM/DBC is a critical factor affecting pollutant transport, providing important insights into the environmental trend and ecological effects of pollutants.

Propofol ameliorates cognitive deficits following splenectomy in aged rats by inhibiting ferroptosis via the SIRT1/Nrf2/GPX4 pathway.

The aim of this study was to investigate the mechanism by which propofol reduces postoperative cognitive dysfunction after splenectomy in aged rats. The rats in the model group and propofol group were subjected to splenectomy, and anesthetized with isoflurane and propofol, respectively. Utilizing the western blotting to assess the expression of sirtuin-1 (SIRT1) in the hippocampus. Molecular docking technology was used to predict the binding ability of propofol and SIRT1. Behavioral tests were performed using the Morris water maze, and the hippocampus was isolated for mechanistic investigations. Molecular docking showed that propofol and SIRT1 had a strong binding affinity. The expression of SIRT1 and its related proteins Nrf2, HO-1, NQO1, and GPX4 in the model rats was decreased compared with the sham group. Moreover, the model group exhibited cognitive decline, such as extended escape latency and decreased number of platform crossings. Pathological analysis showed that the number of apoptotic neurons, the levels of oxidative stress and neuroinflammation, the iron deposition, and the expressions of ACSL4 and TFR1 were increased, while the expressions of SLC7A11 and FTH1 were decreased in the hippocampal CA1 region within the model group. These pathological changes in the propofol group were, however, less than those in the model group. Nevertheless, the SIRT1 inhibitor increased these pathological changes compared with the propofol group. Compared with isoflurane, propofol inhibits ferroptosis in the hippocampus of splenectomized rats by causing less downregulation of the SIRT1/Nrf2/GPX4 pathway, thereby reducing the negative impact on cognitive function.

An mRNA vaccine for pancreatic cancer designed by applying in silico immunoinformatics and reverse vaccinology approaches.

Pancreatic ductal adenocarcinoma is the most prevalent pancreatic cancer, which is considered a significant global health concern. Chemotherapy and surgery are the mainstays of current pancreatic cancer treatments; however, a few cases are suitable for surgery, and most of the cases will experience recurrent episodes. Compared to DNA or peptide vaccines, mRNA vaccines for pancreatic cancer have more promise because of their delivery, enhanced immune responses, and lower proneness to mutation. We constructed an mRNA vaccine by analyzing S100 family proteins, which are all major activators of receptors for advanced glycation end products. We applied immunoinformatic approaches, including physicochemical properties analysis, structural prediction and validation, molecular docking study, in silico cloning, and immune simulations. The designed mRNA vaccine was estimated to have a molecular weight of 165023.50 Da and was highly soluble (grand average of hydropathicity of -0.440). In the structural assessment, the vaccine seemed to be a well-stable and functioning protein (Z score of -8.94). Also, the docking analysis suggested that the vaccine had a high affinity for TLR-2 and TLR-4 receptors. Additionally, the molecular mechanics with generalized Born and surface area solvation analysis of the "Vaccine-TLR-2" (-141.07 kcal/mol) and "Vaccine-TLR-4" (-271.72 kcal/mol) complexes also suggests a strong binding affinity for the receptors. Codon optimization also provided a high expression level with a GC content of 47.04% and a codon adaptation index score 1.0. The appearance of memory B-cells and T-cells was also observed over a while, with an increased level of helper T-cells and immunoglobulins (IgM and IgG). Moreover, the minimum free energy of the mRNA vaccine was predicted at -1760.00 kcal/mol, indicating the stability of the vaccine following its entry, transcription, and expression. This hypothetical vaccine offers a groundbreaking tool for future research and therapeutic development of pancreatic cancer.

An adenine-based metal-organic framework with tailored pore environment for adsorption separation of C2H2 from C2H4 and CO2

The separation of acetylene (C2H2) from mixtures with ethylene (C2H4) and carbon dioxide (CO2) is crucial yet challenging in the chemical industry. Based on the adsorption separation technology, it is desirable to design and develop efficient adsorbents for C2H2 separation. In this work, we present an adenine-based metal-organic framework (Cu-AD-HEA), which features tailored pore environment with Lewis basic sites within the specific intersecting channels for the separation of C2H2 from mixtures with C2H4 and CO2. The obtained Cu-AD-HEA exhibits exceptional adsorption capacity for C2H2 and demonstrates competitive adsorption selectivity for C2H2/C2H4 and C2H2/CO2. Furthermore, dynamic breakthrough results further illustrate the superior dynamic separation of C2H2 over C2H4 and CO2. Moreover, detailed molecular simulations and density functional theory (DFT) calculations elucidate that C2H2 is preferentially captured in a tailored pore environment of Cu-AD-HEA with stronger binding affinity through CH⋯N/O hydrogen bonds and C–H⋯π or π⋯π interactions. This work offers an effective MOF-based adsorbent for the separation of C2H2 from mixtures with C2H4 and CO2.

Exploring the antidiabetic and anti-inflammatory potential of Lavandula officinalis essential oil: In vitro and in silico insights

Medicinal plants have been utilized for centuries in traditional medicine systems worldwide, providing a rich source of bioactive compounds with diverse biological activities. Lavandula officinalis, a member of the Lamiaceae family, has been recognized for its multifaceted pharmacological activities. In this current investigation, our primary objective was to scrutinize the in vitro inhibitory potential of L. officinalis essential oil (LOEO) against alpha-amylase and alpha-glucosidase, with the aim of understanding its antidiabetic effects. Additionally, the assay encompassed tyrosinase and lipoxygenase (LOX) to assess its anti-inflammatory attributes. Unraveling the underlying molecular mechanisms of these activities prompted an in-silico study. The purpose was to establish correlations between in-vitro observations and computational insights derived from molecular docking, which forecasts the interaction of LOEO molecules with their respective targets, alongside ADMET prediction. The Gas Chromatography-Mass Spectrometry (GC-MS) analysis allow to identify eighteen compounds, with the dominance of L−camphor (43.12 %), 1,8−cineole (34.27 %) and borneol (8.60 %) in LOEO. The antidiabetic evaluation revealed that LOEO exhibited noteworthy inhibitory activity against both α-amylase and α-glucosidase, displaying IC50 values of 3.14 ± 0.05 mg/mL and 2.07 ± 0.03 mg/mL, respectively. The subsequent in-silico study highlighted the particularly strong binding affinity of (E)-Farnesene, with a binding score of −7.4 kcal/mol for alpha-glucosidase, while Germacrene D displayed the highest affinity among the ligands (−7.9 kcal/mol) for the alpha-amylase target. Furthermore, the investigation into in vitro anti-inflammatory activity unveiled LOEO efficacy against tyrosinase (IC50 = 42.74 μg/mL) and LOX (IC50 = 11.58 ± 0.07 μg/mL). The in-silico analysis echoed these findings, indicating α-Cadinene's notable binding affinity of 6 kcal/mol with tyrosinase and α-Cedrene's binding score of −6.5 kcal/mol for LOX. Impressively, for both COX-1 and COX-2, α-Cedrene exhibited significant binding affinities of −7.6 and −7.3 kcal/mol, respectively. The convergence between the in vitro and in silico outcomes underscores the potential of LOEO and its constituent compounds as potent inhibitors targeting both diabetes and the inflammatory processes.

Surface Cleaning of Oil Contaminants Using Bulk Nanobubbles.

The removal of oil from solid surfaces, such as textiles and plates, remains a challenge due to the strong binding affinity of the oil. Conventional methods for surface cleaning often require surfactants and mechanical abrasion to enhance the cleaning process. However, in excess, these can pose adverse effects on the environment and to the material. This study investigated how bulk nanobubble water can clean oil microdroplets deposited on surfaces like glass coverslips and dishes. Microscopy imaging and further image analysis clearly revealed that these microdroplets detached from both hydrophobic and hydrophilic surfaces when washed with bulk nanobubble water within a fluidic microchannel. Oil contaminant cleaning was also conducted in water as mobile phase to mimic the circumstances that occur in a dishwasher and washing machine. Cleaning on a larger scale also proved very successful in the removal of oil from a porcelain bowl. These results indicate that nanobubble water can easily remove oil contaminants from glass and porcelain surfaces without the assistance of surfactants. This is in stark contrast to negligible results obtained with a control solution without nanobubbles. This study indicates that nanobubble technology is an innovative, low-cost, eco-friendly approach for oil removal, demonstrating its potential for broad practical applications.

Synthesis and in silico studies of certain benzo[f]quinoline-based heterocycles as antitumor agents

A series of benzoquinoline-employing heterocycles was synthesized by treating 3-chlorobenzo[f]quinoline-2-carbaldehyde with N-phenyl-3-methylpyrazolone, 4-aminoacetophenone, 1,2-diaminoethane, and 2-cyanoethanohydrazide. Also, pyridine, chromene, α,β-unsaturated nitrile, thiosemicarbazone, and 1,2-bis-aryl hydrazine derivatives were prepared from the cyanoethanohydrazone obtained. The DFT calculations and experiment outcomes were consistent. In vitro screening of their antiproliferative efficacy was examined against HCT116 and MCF7 cancer cell lines. The pyrazolone 2 and cyanoethanohydrazone 5 derivatives exhibited the most potency, which was demonstrated by their molecular docking towards the CDK-5 enzyme. The binding energies of compounds 2 and 5 were − 6.6320 kcal/mol (with RMSD of 0.9477 Å) and − 6.5696 kcal/mol (with RMSD of 1.4889 Å), respectively, which were near to that of co-crystallized ligand (EFP). This implies a notably strong binding affinity towards the CDK-5 enzyme. Thus, pyrazolone derivative 2 would be considered a promising candidate for further optimization to develop new chemotherapeutic agents. In addition, the ADME (absorption, distribution, metabolism, and excretion) analyses displayed its desirable drug-likeness and oral bioavailability properties.

Design, synthesis, antimicrobial activity, and mechanism of novel 3-(2,4-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives.

Plant pathogens cause substantial crop losses annually, posing a grave threat to global food security. Fungicides have usually been used for their control, but the rapid development of pesticide resistance renders many ineffective, therefore the search for novel and efficient green pesticides to prevent and control plant diseases has become the top priority in crop planting. The results of bioassay studies indicated that most of the target compounds showed certain antimicrobial activity in vitro. In particular, compound X7 showed high inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC50 value of 27.47 μg mL-1, surpassing conventional control agents such as thiazole zinc (41.55 μg mL-1) and thiodiazole copper (53.39 μg mL-1). Further studies on molecular docking showed that X7 had a strong binding affinity with 2FBW. The morphological change observed by scanning electron microscopy indicated that the surface of Xoo appears wrinkled and cracked under X7 treatment and a total of 2662 proteins were identified by label-free proteomic analysis. Three experiments have elucidated the mechanism whereby X7 induced considerable changes in the physiological and biochemical properties of Xoo, which in turn affected the reproduction and growth of bacteria. This work represents a pivotal advancement, offering important reference for the research and development therapeutics in combating plant pathogens. © 2024 Society of Chemical Industry.

Effects of Kojic Acid-mediated Sonodynamic Therapy as a Matrix Metalloprotease-9 Inhibitor against Oral Squamous Cell Carcinoma: A Bioinformatics Screening and In Vitro Analysis.

Oral squamous cell carcinoma (OSCC) is a type of cancer that is responsible for a significant amount of morbidity and mortality worldwide. Researchers are searching for promising therapeutic methods to manage this cancer. In this study, an in silico approach was used to evaluate the activity of sonodynamic therapy (SDT) based on the use of Kojic acid as a sonosensitizer to inhibit matrix metalloprotease-9 (MMP-9) in OSCC. The three-dimensional structure of MMP-9 was predicted and validated by computational approaches. The possible functional role of MMP-9 was determined in terms of Gene Ontology (GO) enrichment analysis. In silico, molecular docking was then performed to evaluate the binding energies of Kojic acid with MMP-9, and ADME parameters and toxicity risks were predicted. The pharmacokinetics and drug-likeness properties of Kojic acid were assessed. Moreover, after the determination of the cytotoxicity effect of Kojic acid-mediated SDT, the change of mmp-9 gene expression was assessed on OSCC cells. The results of the study showed that Kojic acid could efficiently interact with MMP-9 protein with a strong binding affinity. Kojic acid obeyed Lipinski's rule of five without violation and exhibited drug-likeness. The cytotoxic effects of Kojic acid and ultrasound waves on the OSCC cells were dose-dependent, and the lowest expression level of the mmp-9 gene was observed in SDT. Overall, Kojic acid-mediated SDT as an MMP-9 inhibitor can be a promising adjuvant treatment for OSCC. The study highlights the potential of In silico approaches to evaluate therapeutic methods for cancer treatment.

Increased Uptake of 18 F-THK5351 in Isocitrate Dehydrogenase-Wildtype Glioblastoma But Not in Meningioma.

18 F-THK5351 demonstrates a strong binding affinity and selectivity for tau. However, off-target binding with monoamine oxidase-B enzyme, highly expressed in the outer mitochondrial membranes of astrocytes, is possible. In a case with isocitrate dehydrogenase-wildtype glioblastoma, 11 C-MET PET and 18 F-THK5351 PET exhibited increased uptake in the tumor. Conversely, in another case with intracranial meningioma, MET PET revealed increased uptake in the tumor, whereas 18 F-THK5351 PET showed no abnormal uptake in the tumor. However, it is challenging to distinguish meningiomas from glioblastomas on MRI. 18 F-THK5351 PET might help differentiate between isocitrate dehydrogenase-wildtype glioblastoma and meningioma.

Immuno-informatics study identifies conserved T cell epitopes in non-structural proteins of Bluetongue virus serotypes: formulation of a computationally optimized next-generation broad-spectrum multi-epitope vaccine.

Bluetongue (BT) poses a significant threat to the livestock industry, affecting various animal species and resulting in substantial economic losses. The existence of numerous BT virus (BTV) serotypes has hindered control efforts, highlighting the need for broad-spectrum vaccines. In this study, we evaluated the conserved amino acid sequences within key non-structural (NS) proteins of BTV and identified numerous highly conserved murine- and bovine-specific MHC class I-restricted (MHC-I) CD8+ and MHC-II-restricted CD4+ epitopes. We then screened these conserved epitopes for antigenicity, allergenicity, toxicity, and solubility. Using these epitopes, we developed in silico-based broad-spectrum multiepitope vaccines with Toll-like receptor (TLR-4) agonists. The predicted proinflammatory cytokine response was assessed in silico using the C-IMMSIM server. Structural modeling and refinement were achieved using Robetta and GalaxyWEB servers. Finally, we assessed the stability of the docking complexes through extensive 100-nanosecond molecular dynamics simulations before considering the vaccines for codon optimization and in silico cloning. We found many epitopes that meet these criteria within NS1 and NS2 proteins and developed in silico broad-spectrum vaccines. The immune simulation studies revealed that these vaccines induce high levels of IFN-γ and IL-2 in the vaccinated groups. Protein-protein docking analysis demonstrated promising epitopes with strong binding affinities to TLR-4. The docked complexes were stable, with minimal Root Mean Square Deviation and Root Mean Square Fluctuation values. Finally, the in silico-cloned plasmids have high % of GC content with > 0.8 codon adaptation index, suggesting they are suitable for expressing the protein vaccines in prokaryotic system. These next-generation vaccine designs are promising and warrant further investigation in wet lab experiments to assess their immunogenicity, safety, and efficacy for practical application in livestock. Our findings offer a robust framework for developing a comprehensive, broad-spectrum vaccine, potentially revolutionizing BT control and prevention strategies in the livestock industry.

Variations in the expression of odorant binding and chemosensory proteins in the developmental stages of whitefly Bemisia tabaci Asia II-1

The cotton whitefly, Bemisia tabaci, is considered as a species complex with 46 cryptic species, with Asia II-1 being predominant in Asia. This study addresses a significant knowledge gap in the characterization of odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) in Asia II-1. We explored the expression patterns of OBPs and CSPs throughout their developmental stages and compared the motif patterns of these proteins. Significant differences in expression patterns were observed for the 14 OBPs and 14 CSPs of B. tabaci Asia II-1, with OBP8 and CSP4 showing higher expression across the developmental stages. Phylogenetic analysis reveals that OBP8 and CSP4 form distinct clades, with OBP8 appearing to be an ancestral gene, giving rise to the evolution of other odorant-binding proteins in B. tabaci. The genomic distribution of OBPs and CSPs highlights gene clustering on the chromosomes, suggesting functional conservation and evolutionary events following the birth-and-death model. Molecular docking studies indicate strong binding affinities of OBP8 and CSP4 with various odour compounds like β-caryophyllene, α-pinene, β-pinene and limonene, reinforcing their roles in host recognition and reproductive functions. This study elaborates on our understanding of the putative roles of different OBPs and CSPs in B. tabaci Asia II-1, hitherto unexplored. The dynamics of the expression of OBPs and CSPs and their interactions with odour compounds offer scope for developing innovative methods for controlling this global invasive pest.

Green synthesis of bismuth vanadate nanostructures for efficient photocatalytic and biological studies

In the current investigation, BiVO4 nanoparticles were prepared via a simple combustion approach followed by annealing at 400°C using rain tree pod extract. The physicochemical and morphological features were examined through spectroscopic techniques. Optical studies were carried out using a UV–visible spectrophotometer, revealing a bandgap of 2.4 eV. Photocatalytic efficiency was assessed through degradation studies using methylene blue (MB) dye under visible photon irradiation, demonstrating an impressive 94 % degradation rate. Consequently, this synthesized bismuth vanadate serves as an outstanding photocatalyst under visible irradiation. Furthermore, these nanoparticles exhibited favorable responses in antifungal, antibacterial, and molecular docking studies. Bismuth vanadate nanoparticles had substantial antifungal efficacy, with the Bi2 version successfully suppressing Aspergillus Niger at a 50 % concentration. At 100 mg/ml, Bi2 showed a 6 mm zone of inhibition against Gram-positive Staphylococcus aureus and a 5 mm zone against Gram-negative Escherichia coli for antibacterial evaluation. The protein 7BLY and Bismuth vanadate had four hydrogen bond interactions and a strong binding affinity, as shown by molecular docking, of −5.0 Kcal/mol. Therefore, bismuth vanadate nanoparticles synthesized through green methods show promise in combating fungal and bacterial infections, as well as potential applications in various fields.

Development of epitope-based vaccine to prevent Marburg virus infection: an in silico approach

Marburg virus (MARV) is one of the deadliest zoonotic viruses, causing severe hemorrhagic fever in humans with high mortality rates. The development of an effective vaccine is crucial to prevent potential Marburg virus outbreaks. In this study, an in silico approach was employed to design an epitope-based vaccine to prevent MARV infections. The MARV proteins nominating NP, VP24, VP35, VP30, VP40, GP & Polymerase L was analyzed for antigenicity and non-allergenicity prediction, among these proteins VP30 protein has a 0.5636 (Probable Antigen) score and it was non-allergen. For that reason, VP30 was selected for further in silico analysis. After analysis it is found that the top ranked T–cell (MHC-I) epitopes LSKPPPPPK, ESSPTNHIPR, TQLPSKPHY, SPQDCGSPSL, FEAALWQGW, T-Cell (MHC-II) epitopes IHLDKGGQF, INTMTELHM, VTPTIYHET, YTNYHPRAR, YTGIHLDKG was epitopes & B-Cell epitopes SEIGKLDET, IHLDKGGQF, MNHENLPQDQNGV, PTCNRDHDLDNLTN was found non-toxic and non-allergen. The T-Cell (MHC-I)epitope TQLPSKPHY,T-Cell (MHC-II)epitope YTNYHPRAR & B-Cell epitope SEIGKLDET was found highly antigenic, non-toxic as well as non-allergen and it was selected for molecular docking analysis. The T-Cell (MHC-I) epitope TQLPSKPHY,T-Cell (MHC-II)epitope YTNYHPRAR shows strong structural similarity and potential binding affinity with antibody. The B-Cell epitope SEIGKLDET shows poor affinity towards antibody. In silico analysis indicate that both T-Cell epitopes becomes an effective peptide vaccine to prevent MARV infection. Our findings highlight the promise of in silico vaccine design in accelerating the development of vaccines against MARV, a highly pathogenic virus with no effective cure currently available

Catalpol alleviates heat stroke-induced liver injury in mice by downregulating the JAK/STAT signaling pathway

BackgroundHeat stroke (HS) generated liver injury is a lethal emergency that occurs when the body is exposed to temperatures up to 40 °C for a few hours. PurposeThis study aimed to evaluate the therapeutic prospects of Catalpol (CA) from the blood-cooling herb Rehamanniae Radix on liver injury by HS. Study design and methodsA murine HS model (41 ± 0.5 °C, 60 ± 5 % relative humidity) and two cell lines (lipopolysaccharide + 42 °C) were used to assess the protective effects of CA on physiological, pathological, and biochemical features in silico, in vivo, and in vitro. ResultsCA treatment significantly improved survival rates in vivo and cell viability in vitro over those of the untreated group. Additionally, CA treatment reduced core body temperature, enhanced survival time, and mitigated liver tissue damage. Furthermore, CA treatment also reduced the activities of AST and ALT enzymes in the serum samples of HS mice. Molecular docking analysis of the 28 overlapping targets between HS and CA revealed that CA has strong binding affinities for the top 15 targets. These targets are primarily involved in nine major signaling pathways, with the JAK-STAT pathway being highly associated with the other eight pathways. Our findings also indicate that CA treatment significantly downregulated the expression of proinflammatory cytokines both in vivo and in vitro while upregulating the expression of anti-inflammatory cytokines. Moreover, CA treatment reduced the levels of JAK2, phospho-STAT5, and phospho-STAT3 both in vivo and in vitro, which is consistent with its inhibition of the apoptotic markers p53, Bcl2, and Bax. ConclusionsHeat stroke-induced liver injury was inhibited by CA through the downregulation of JAK/STAT signaling.

Theoretical studies of phytochemicals with feline infectious peritonitis virus proteins: a search for novel antivirals

Feline Infectious Peritonitis Virus (FIPV) is a highly lethal pathogen affecting cats worldwide. Developing effective antiviral treatments is crucial for managing this disease. This study investigates the potential of flavonoids to act as antiviral agents and allosteric modulators against the FIPV spike protein using molecular docking simulations. Thirteen flavonoids were docked against the FIPV spike protein (PDB ID: 6JX7) in both ligand-free (cleaned) and ligand-bound (uncleaned) states to assess their binding affinities and potential allosteric effects. The docking results revealed that all tested flavonoids exhibited strong binding affinities, with docking scores ranging from -7.9 to -9.6 kcal/mol in the cleaned receptor state. Notably, Hesperidin, Morin, Hesperetin, and Quercetin maintained or even improved their binding affinities in the presence of native ligands, suggesting their potential as allosteric modulators. Comparative analysis of the binding modes in the cleaned and uncleaned receptor states further supports the allosteric modulator potential of Morin, Hesperetin, and Hesperidin. These findings highlight the promising role of flavonoids as antiviral agents and allosteric modulators targeting the FIPV spike protein. Further experimental validation and optimization of these compounds could lead to the development of effective treatments for feline infectious peritonitis. This study provides valuable insights into the application of flavonoids in the management of viral diseases and contributes to the ongoing efforts in antiviral drug discovery.

Investigating Pyruvate Dehydrogenase Kinase 3 Inhibitory Potential of Myricetin Using Integrated Computational and Spectroscopic Approaches.

Protein kinases are involved in various diseases and currently represent potential targets for drug discovery. These kinases play major roles in regulating the cellular machinery and control growth, homeostasis, and cell signaling. Dysregulation of kinase expression is associated with various disorders such as cancer and neurodegeneration. Pyruvate dehydrogenase kinase 3 (PDK3) is implicated in cancer therapeutics as a potential drug target. In this current study, a molecular docking exhibited a strong binding affinity of myricetin to PDK3. Further, a 100 ns all-atom molecular dynamics (MD) simulation study provided insights into the structural dynamics and stability of the PDK3-myricetin complex, revealing the formation of a stable complex with minimal structural alterations upon ligand binding. Additionally, the actual affinity was ascertained by fluorescence binding studies, and myricetin showed appreciable binding affinity to PDK3. Further, the kinase inhibition assay suggested significant inhibition of PDK3 by myricetin, revealing an excellent inhibitory potential with an IC50 value of 3.3 μM. In conclusion, this study establishes myricetin as a potent PDK3 inhibitor that can be implicated in therapeutic targeting cancer and PDK3-associated diseases. In addition, this study underscores the efficacy of myricetin as a potential lead to drug discovery and provides valuable insights into the inhibition mechanism, enabling advancements in cancer therapeutics.

Computational investigation of nanoemulsion-released tocopherol for treating cardiovascular diseases: Insights from molecular dynamic simulation and deep learning prediction

This research investigated the potential of tocopherol released from nanoemulsion as a therapeutic agent for cardiovascular diseases (CVD) through comprehensive in-silico site-specific molecular docking analysis and AI- driven Molecular Dynamic Simulation, between tocopherol and seven CVD-related proteins (Angiotensin Converting Enzyme (ACE) (1O8a), Human Angiotensin Receptor (4YAY), P38 Mitogen-Activated Protein Kinase (MAPK) (4DLI), HMG-CoA Reductase (1HW9), β-1-Adrenergic Receptor (2YCW), Human C-reactive Protein (1BO9), and Cyclooxygenase-2 (1CX2)). Our findings revealed significant interactions. α-Tocopherol exhibited strong binding affinities, particularly with the 2YCW protein, evidenced by a Vina score of -11.9 ± 0.86 kcal/mol and an inhibition constant of 1.4 ± 0.12 µM. Extensive hydrophobic interactions and significant hydrogen bonds were identified as critical for the stability of these complexes. Furthermore, Molecular Dynamics (MD) simulations, RMSD, Rg, RMSF, and Free Energy Landscape (FEL) profiles, and a deep convolutional neural network (CNN) used for predicting interaction sites from protein sequences, illustrated that the protein-ligand complexes attained dynamic configuration stability with RMSD values converging around 0.3 nm, underscoring the robustness of tocopherol-protein interactions. The pathway analysis highlights the possibility of tocopherol's involvement in interacting with several key biological pathways, Dilated Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, Hypertrophic Cardiomyopathy, and Apoptosis.This study revealed significant insights into the interactions of Nanoemulsion-released tocopherol with key proteins involved in the development of cardiovascular diseases, aimed at improving cardiovascular health. However, the findings of the study require meticulous experimental study and clinical trials to provide accurate results and validate tocopherol's therapeutic efficacy.

Chemoenzymatic synthesis of sialyl-α2,3-lactoside–functionalized BSA conjugate inhibits influenza infection

Influenza remains a global public health threat, and the development of new antivirals is crucial to combat emerging drug-resistant influenza strains. In this study, we report the synthesis and evaluation of a sialyl lactosyl (TS)–bovine serum albumin (BSA) conjugate as a potential multivalent inhibitor of the influenza virus. The key trisaccharide component, TS, was efficiently prepared via a chemoenzymatic approach, followed by conjugation to dibenzocyclooctyne-modified BSA via a strain-promoted azide-alkyne cycloaddition reaction. Biophysical and biochemical assays, including surface plasmon resonance, isothermal titration calorimetry, hemagglutination inhibition, and neuraminidase inhibition, demonstrated the strong binding affinity of TS-BSA to the hemagglutinin (HA) and neuraminidase (NA) proteins of the influenza virus as well as intact virion particles. Notably, TS-BSA exhibited potent inhibitory activity against viral entry and release, preventing cytopathic effects in cell culture. This multivalent presentation strategy highlights the potential of glycocluster-based antivirals for combating influenza and other drug-resistant viral strains.

High-throughput virtual screening of Streptomyces spp. metabolites as antiviral inhibitors against the Nipah virus matrix protein

Nipah virus (NiV) remains a significant global concern due to its impact on both the agricultural industry and human health, resulting in substantial economic and health consequences. Currently, there is no cure or commercially available vaccine for the virus. Therefore, it is crucial to prioritize the discovery of new and effective treatment options to prevent its continued spread. Streptomyces spp. are rich sources of metabolites known for their bioactivity against certain diseases; however, their potential as antiviral drugs against the Nipah virus remain unexplored. In this study, 6524 Streptomyces spp. metabolites were screened through in silico methods for their inhibitory effects against the Nipah virus matrix (NiV-M) protein, which assists in virion assembly of Nipah virus. Different computer-aided tools were utilized to carry out the virtual screening process: ADMET profiling revealed 913 compounds with excellent safety and efficacy profiles, molecular docking predicted the binding poses and associated docking scores of the ligands in their respective targets, MD simulations confirmed the binding stability of the top ten highest-scoring ligands in a 100 ns all-atom simulation, PCA elucidated simulation convergence, and MMPB(GB)SA calculations estimated the binding energies of the final candidate compounds and determined the key residues crucial for complex formation. Using in silico methods, we identified six metabolites targeting the main substrate-binding site and five targeting the dimerization site that exhibited excellent stability and strong binding affinity. We recommend testing these compounds in the next stages of drug development to confirm their effectiveness as therapeutic agents against Nipah virus.