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Low‐basicity fluorine‐containing mold flux, which forms a porous slag film with NaF pores, is expected to solve the contradiction between heat transfer and lubrication in the continuous casting of peritectic steel. Herein, the kinetic mechanism and the influence of NaF gas formation based on the different fluorine raw materials (NaF, CaF2, and Na3AlF6) at 0.9 basicity and 6 wt% fluorine are investigated by the combination of experiments and calculations. The results show that CaF2 is the first to generate NaF gas at 1189 K, followed by Na3AlF6 (1238 K) and NaF (1328 K). NaF raw material produces the most NaF gas with the lowest activation energy in the three raw materials, due to high Na ion kinetic energy, the simple degree of polymerization, and Na‐F1 bonds. Correspondingly, NaF bubbles in the molten slag are the largest based on their aggregation. Na3AlF6 and CaF2 raw materials rank second and third, with F atoms primarily bonded as Al‐Fx and Ca‐Fx and the higher proportion of QSi−O−Al2$Q_{\text{Si} - \text{O} - \text{Al}}^{2}$ and QSi−O−Si4$Q_{\text{Si} - \text{O} - \text{Si}}^{4}$ structure. Notably, at 0.9 basicity and 6 wt% fluorine, Na3AlF6 as raw material generates a suitable amount of gas, making diffuse and fine NaF bubbles in the molten slag. [ABSTRACT FROM AUTHOR]

Poly(ADP‐ribose) polymerase‐10 (PARP10) is a critical enzyme involved in DNA damage repair. Its function in cellular repair mechanisms has been implicated in the development of chemoresistance and radioresistance in cancer cells. Consequently, PARP10 inhibition represents a promising, albeit challenging, and therapeutic target for various cancer types. This study aims to discover new PARP10 potential inhibitors via a hybrid of in silico approaches. Initially, pharmacophore‐based virtual screening was conducted on the ZINC and NCI databases. The resulting compounds were subsequently subjected to molecular docking studies to identify potential new PARP10 inhibitors. Subsequently, classical molecular dynamics (MD) simulations were conducted to evaluate and compare the dynamic behavior of the selected ligand, veliparib, and OUL35, a selective PARP10 inhibitor. Ultimately, compound ZINC20906412 was found as a potential lead compound based on its docking score and favorable interactions within the PARP10 active site. This compound may offer therapeutic potential for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, one of the most often diagnosed malignancies worldwide, continues to take countless women's lives. Its treatment usually involves targeting the human estrogen receptor alpha (ERα). Current research explores the potential of natural compounds to regulate ERα activity, providing a hopeful direction for breast cancer therapy. Our study utilized a comprehensive approach to identify promising natural compounds for breast cancer treatment, including quantum descriptors, molecular docking, molecular dynamics simulations, and ADMET/pharmacokinetics analysis. Results: Six natural compounds derived from podophyllum medicinal plants, namely 4-demethylpodophyllotoxin (NP1), α-peltatin (NP2), podophyllotoxin (NP3), deoxypodophyllotoxin (NP4), podophyllotoxone (NP5), and β-peltatin (NP6), were investigated as potential selective estrogen receptor α (ERα) inhibiting agents for breast cancer. These compounds demonstrated the strongest binding affinity to the target enzyme, with binding energies of − 8.9 and − 8.1 kcal/mol, respectively. Further assessments of drug-likeness and ADME properties were conducted for these compounds, along with quantum calculations (HOMO–LUMO) to evaluate their reactivity. Additionally, molecular dynamics studies were performed to assess the stability of the NP1 and NP2 protein–ligand complexes. Conclusions: We analyzed six natural compounds comprehensively, evaluating their ADME properties, molecular docking interactions, quantum descriptors, and dynamic simulations. Our findings demonstrate that these natural compounds are promising possibilities for treating breast cancer. Additionally, they may provide a basis for developing future compounds targeting estrogen receptor α (ERα) activity. [ABSTRACT FROM AUTHOR]

ABSTRACT The human papillomavirus (HPV) 33 is a high‐risk strain that causes lesions with potential cancerous outcomes. Its E2 protein regulates the viral protein transcription and life cycle maintenance. The DNA binding domain (DBD) of the E2 protein plays a crucial role in the viral life cycle. The DBD region of the E2 protein is particularly interesting for targeting and finding potential inhibitors to inhibit its function or dimerization. Given the limited research on HPV 33 and its proteins, the present work delved into the interaction of two natural polyphenolic compounds, resveratrol, and baicalein, with the E2 DBD of HPV 33 using biophysical and in silico studies. Fluorescence studies of the E2 DBD‐polyphenol complexes showed fluorescence quenching with a binding constant of the order of 106 M−1. Circular dichroism data reveal conformational changes upon binding with the polyphenols, possibly due to distinct binding sites of the E2 DBD. Differential scanning calorimetry exhibited higher melting temperatures for the two complexes than alone DBD, suggesting the complexes' stability. ITC experiment suggested favorable binding reactions with kd values in the micromolar range. Molecular docking and dynamic simulation studies revealed that the resveratrol binds to the helical region and baicalein near the central dimeric interface of E2 DBD with a good binding affinity, forming a stable protein‐ligand complex during the run of 100 ns simulation. Therefore, the current study identifies both polyphenolic compounds as promising candidates for potential antiviral drug development. [ABSTRACT FROM AUTHOR]

In recent years, hepatitis B virus (HBV) core protein allosteric modulators (CpAMs) have become a hot spot to develop new anti‐HBV drugs. Sulfonamide analogues are a new class of CpAMs targeting HBV core protein (Cp), while their biological activity is still needed to be improved and the binding mechanism is unclear still. In this study, we utilized molecular docking and molecular dynamics simulation to explore the binding mode between the novel compounds and HBV Cp. Combining with binding free energy calculation and decomposition, we inferred that TyrE132, ValE124, ThrE128, ThrD109, and IleD105 were key residues during the binding process, and especially, the conformational change of TryE132 was responsible for the stable binding. Besides, reasonable CoMFA (q2 = 0.515, r2ncv = 0.994, and r2pred = 0.628) and CoMSIA (q2 = 0.602, r2ncv = 0.988, and r2pred = 0.681) models were constructed to explore the 3D structure‐activity relationship of the novel compounds. The results suggested that it was favorable to increase the biological activity of sulfonamide analogues when introducing hydrophobic groups to R1 and electronegative groups to R2. In conclusion, we explored the binding mode and structure‐activity relationship between sulfonamides and HBV Cp and provided a theoretical basis for the optimization of this series of compounds. [ABSTRACT FROM AUTHOR]

The non-ideal accuracy and insufficient selectivity of CRISPR/Cas9 systems is a serious problem for their use as a genome editing tool. It is important to select the target sequence correctly so that the CRISPR/Cas9 system does not cut similar sequences. This requires an understanding of how and why mismatches in the target sequence can affect the efficiency of the Cas9/sgRNA complex. In this work, we studied the catalytic activity of the Cas9 enzyme to cleave DNA substrates containing nucleotide mismatch at different positions relative to the PAM in the "seed" sequence. We show that mismatches in the complementarity of the sgRNA/DNA duplex at different positions relative to the protospacer adjacent motif (PAM) sequence tend to decrease the cleavage efficiency and increase the half-maximal reaction time. However, for two mismatches at positions 11 and 20 relative to the PAM, an increase in cleavage efficiency was observed, both with and without an increase in half-reaction time. Thermodynamic parameters were obtained from molecular dynamics results, which showed that mismatches at positions 8, 11, and 20 relative to the PAM thermodynamically stabilize the formed complex, and a mismatch at position 2 of the PAM fragment exerts the greatest stabilization compared to the original DNA sequence. The weak correlation of the thermodynamic binding parameters of the components of the Cas9/sgRNA:dsDNA complex with the cleavage data of DNA substrates containing mismatches indicates that the efficiency of Cas9 operation is mainly affected by the conformational changes in Cas9 and the mutual arrangement of sgRNA and substrates. [ABSTRACT FROM AUTHOR]

Polystyrene (PS) is a thermoplastic polymer commonly used in various applications due to its bulk properties. Designing functional polystyrenes with well-defined structures for targeted applications is of significant interest due to the rigid and apolar nature of the polymer chain. Progress is hindered to date by the limitations of current analytical methods in defining the atomistic-level folding of the polymer chain. The integration of ion mobility spectrometry and molecular dynamics simulations is beneficial in addressing these challenges. However, data on gas-phase polystyrene ions are rarely reported in the literature. We herein investigate the gas phase structure of polystyrene ions with different end groups to establish how the nature and the rigidity of the monomer unit affect the charge stabilization. We find that, in contrast to polar polymers in which the charges are located deep in the ionic globules, the charges in the PS ions are rather located at the periphery of the polymer backbone, leading to singly and doubly charged PS ions adopting dense elliptic-shaped structures. Molecular dynamics (MD) simulations indicate that the folding of the PS rigid chain is controlled by phenyl ring interactions with the charge ultimately remaining excluded from the core of the globular ions, whereas the folding of polyether ions is initiated by the folding of the flexible polyether chain around the sodium ion that remains deeply enclosed in the core of the ions. [ABSTRACT FROM AUTHOR]

An in-depth investigation was undertaken to explore the ground-state molecular and electronic structure of Dimethyl 5-hydroxybenzene-1,3-dicarboxylate (D5HD). The potential energy scan of D5HD at various dihedral angles identified the lowest energy conformer, which was re-optimised at the higher basis set. The recorded FT-Raman and FT-IR spectra were compared with corresponding theoretical spectra, demonstrating a high degree of coherence. A comprehensive Natural Bond Orbital analysis was done for D5HD to gain insights for the overall electronic distribution within the molecule. Additionally, nonlinear optical (NLO) properties along with various DFT-based descriptors were calculated. Molecular docking studies against human acetylcholinesterase enzyme (PDB 2JF0), D5HD displayed good binding affinity. The study revealed that hydrogen bonded as well as van der Waals interactions exist between D5HD and different residues in the binding cavity of the target protein. The 100 ns MD simulation confirms the conformational stability of protein (2JF0)–ligand (D5HD) complex. The binding energy and residue decomposition analysis performed using MM-GBSA approach showed positive results with binding energy of −17.76 kcal/mol. Furthermore, D5HD effectively passed all pharmacokinetic filters, establishing its potential as a promising candidate in the quest for novel acetylcholinesterase inhibitors. Highlights: Systematic exploration of the structure and spectroscopic properties of D5HD. Molecular docking between D5HD and acetylcholinesterase (PDB 2JF0) reveals the establishment of hydrogen bonds and Van der Waals interactions. D5HD successfully complies with all relevant pharmacokinetic filters. MD simulation analysis on 2JF0–D5HD complex confirms the conformational stability. Energy and residue decomposition based on MMGBSA approach. [ABSTRACT FROM AUTHOR]

Diabetes mellitus has emerged as a pressing global public health concern in the 21st century, necessitating the exploration of effective and safer therapeutic alternatives to conventional synthetic anti-diabetic medications. This study aimed to comprehensively evaluate the anti-diabetic potential of Castanopsis tribuloide s through a multi-faceted approach encompassing in vitro , in vivo , and in silico experiments. In vitro assessments revealed that the methanol extract of C. tribuloides bark (CtbME) exhibited remarkable α-glucosidase inhibitory activity, as demonstrated by a low IC 50 value of 550 μg/mL, surpassing that of acarbose (600 μg/mL). Furthermore, CtbME administration led to a significant and dose-dependent reduction in hyperglycemic blood glucose levels. Twenty-three secondary metabolites were identified in GC-MS analysis. Molecular docking analysis was employed to elucidate the molecular interactions between C. tribuloides constituents and α-glucosidase. Rutin hydrate, catechin hydrate, and betulin exhibited higher binding affinity than acarbose, where rutin hydrate demonstrated exceptional stability throughout molecular dynamics simulation (MDS), affirming the accuracy of the docking data. The findings of this research underscore the potential of C. tribuloides as a source of anti-diabetic agents and provide valuable insights into the molecular mechanisms underlying its efficacy. [Display omitted] • CtbME exhibited remarkable α-glucosidase inhibitory activity. • CtbME significantly reduced hyperglycemic blood glucose levels in diabetic mice. • GC-MS analysis of CtbME identified 23 secondary metabolites. • Rutin hydrate and betulin showed strong binding affinity to α-glucosidase. • The α-glucosidase inhibitory mechanism was confirmed by MD simulation. [ABSTRACT FROM AUTHOR]

A cell’s ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3’ end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease. [ABSTRACT FROM AUTHOR]

Monopolar spindle kinase 1 (MPS1, also called TTK) is an attractive target for the treatment of cancers. Five MPS1 inhibitors have entered the clinical trials, but four of them were discontinued; thus, it is necessary to develop MPS1 inhibitors with novel scaffolds. In the present work, several computational tools were built to design MPS1 inhibitors. The deep recurrent neural network was used for generating potential highly active MPS1 inhibitors. The deep neural network was used to build a ligand-based consensus model for distinguishing the highly and weakly active MPS1 inhibitors. Five co-crystal structures were used to develop the consensus docking score for distinguishing actives and decoys. The ligand-based consensus model and the consensus docking score were used to evaluate the generated molecules, and finally, two scaffolds, which were less reported as MPS1 inhibitors previously, were selected. A total of 15 compounds with the two scaffolds were synthesized and tested by in vitro enzymatic inhibition assays. Five compounds had sub-micromolar to low micromolar in vitro potencies, and the most active compound was 10 with an IC50 of 556 nM. The binding modes of the new compounds were revealed by molecular dynamic simulations. We believe that the computational strategies in the present work were helpful for discovering new potential scaffolds. [ABSTRACT FROM AUTHOR]

ABSTRACT Antimicrobial resistance is one of the biggest threats to public health across the globe. Bacteria, fungi, viruses, and protozoans have been exhibiting resistance against antimicrobial drugs making them ineffective. Hence, the development of new antibiotics with a different mode of action is highly desirable. In this study, 10 new chromone‐incorporated fused thiazolo[2,3‐b]quinazolinone derivatives, 8a‐j, have been prepared via Biginelli reaction involving aromatic aldehydes, 1‐tetralone, and thiourea followed by a reaction with 2‐chloro‐N‐phenylacetamide, and Knoevenagel condensation with 3‐formylchromone. All the structures of the compounds were characterized by NMR, FTIR, and mass spectrometry. The in vitro antibacterial activities of all the synthesized compounds against the four different microbial strains were evaluated. Among them, few compounds demonstrated prominent activity against Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa. No appreciable activity of any compound against Klebsiella pneumoniae was observed. Molecular docking studies were employed to reveal the interactions responsible for the potent compounds' activities against S. aureus, S. pyogenes, and P. aeruginosa. Both in vitro and in silico studies have been carried out by using standard agar well diffusion protocol and Auto Dock Vina in PyRx. The results indicated that compound 8c was the potential compound as it showed good affinity toward the receptors of all three organisms. Molecular dynamics simulation of the 8c‐1JIJ complex for 100 ns further confirmed the potentiality of 8c. The pharmacokinetic properties of the compounds indicate that the studied molecules have exhibited a favorable profile. [ABSTRACT FROM AUTHOR]

Reactive multilayer nanofoils (RMNFs), comprised of alternating layers of metals such as nickel and aluminum, have emerged as a focal point of interest owing to their distinctive properties and versatile applications across semiconductor and micro-electromechanical systems. This nanoengineered material undergoes a self-contained exothermic reaction, initiated by a small external trigger delivering localized heat up to 1500 ℃ in fractions of a second. It can be a heat source material primarily used to make a bond between electric components by melting solders. However, the volume shrinkage during reaction causes void formation and microcracking in the reaction product, and it reduces the reliability of the bonding. In this study, we systematically investigate 11 different Ni–Al RMNFs, including multilayers with 0, 10, 30, 50, 70, and 90% alloyed regions (polycrystalline B2-NiAl or amorphous-NiAl) using molecular dynamic simulations. We found that samples with alloyed interlayers exhibit reduced reaction temperatures and volume shrinkage after the reaction. By controlling the thickness of the alloyed interlayers and structures, we can reduce the damage caused by volume shrinkage during the reaction while obtaining a sufficient reaction temperature. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays a pivotal role in the development and progression of neurodegenerative diseases, with a complex interplay between immune responses and brain activity. Understanding this interaction is crucial for identifying therapeutic targets and developing effective treatments. This study aimed to explore the neuroprotective properties of flavonoid compounds from Spondias mombin via the modulation of neuroinflammatory pathway using a comprehensive in-silico approach, including network pharmacology, molecular docking, and dynamic simulations. Active flavonoid ingredients from S. mombin were identified, and their potential protein targets were predicted through Network Pharmacology. Molecular docking was conducted to determine the binding affinities of these compounds against targets obtained from network pharmacology, prioritizing docking scores ≥ − 8.0 kcal/mol. Molecular dynamic simulations (MDS) assessed the stability and interaction profiles of these ligand–protein complexes. The docking study highlighted ≥ − 8.0 kcal/mol for the ligands (catechin and epicatechin) against FYN kinase as a significant target. However, these compounds failed the blood–brain barrier (BBB) permeability test. MDS confirmed the stability of catechin and the reference ligand at the FYN kinase active site, with notable interactions involving hydrogen bonds, hydrophobic contacts, and water bridges. GLU54 emerged as a key residue in the catechin-FYN complex stability due to its prolonged hydrogen bond interaction. The findings underscore the potential of S. mombin flavonoids as therapeutic agents against neuroinflammation, though optimization and nanotechnology-based delivery methods are suggested to enhance drug efficacy and overcome BBB limitations. [ABSTRACT FROM AUTHOR]

Background: Although potato virus Y (PVY) is the most serious virus-infecting potato plants worldwide, the losses concurred by it remain unmanageable due to the lack of efficient anti-PVY agents. Hence, the objective of this study was to assess the antiviral properties of secondary metabolite compounds obtained from culture filtrates of four Trichoderma spp. isolates. The assessment was conducted using computational methods, including molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, as well as molecular dynamics simulations. The aim was to develop novel and effective agents for combating PVY. Results: The GC–MS analysis of the studied Trichoderma spp. secondary metabolites revealed 24 compounds with relative amounts exceeding 10%. Molecular docking was then performed using MOE software to evaluate the activity of these compounds against the PVY protein coat (PDB-ID: 6HXX). Ningnanmycin and ribavirin, known plant virus inhibitors, were employed as reference ligands for comparison. Among the compounds tested, C9, C10, C13, and C19 exhibited superior docking scores, root mean square deviation (RMSD) values, and binding modes compared to the reference ligands. In addition, these compounds successfully passed the ADMET analysis. Further investigation focused on compounds C13 and C19, which underwent in-depth analysis through MDs for 100 ns. The MDs trajectories demonstrated that both complexes exhibited favorable stability, compactness, and binding modes throughout the simulation period. However, the C19/PVY-CP complex outperformed the C13 complex in all calculated parameters such as RMSD, root mean square fluctuation (RMSF), radius of gyration (RoG), solvent-accessible surface area (SASA), and intermolecular hydrogen bonds. Interestingly, these findings aligned with the results obtained from the docking analysis, indicating that C9 and C10 possess high potential against PVY, as they exhibited binding modes like that of C19. Conclusion: These promising outcomes provide a solid foundation for considering the potential use of compounds C9, C10, C13, and C19 as antiviral agents. Further experimental validation and in-depth studies are warranted to assess the efficacy and safety of these compounds and their potential as antiviral therapeutics. To our knowledge, this is the first report to study the biological activities of the Trichoderma-based bioactive compounds against PVY using computational techniques. [ABSTRACT FROM AUTHOR]

Cytochrome c (CytC), a one-electron carrier, transfers electrons from complex bc1 to cytochrome c oxidase (CcO) in the electron-transport chain. Electrostatic interaction with the partners, complex bc1 and CcO, is ensured by a lysine cluster near the heme forming the Universal Binding Site (UBS). We constructed three mutant variants of mitochondrial CytC with one (2Mut), four (5Mut), and five (8Mut) Lys->Glu substitutions in the UBS and some compensating Glu->Lys substitutions at the periphery of the UBS for charge compensation. All mutants showed a 4–6 times increased peroxidase activity and accelerated binding of cyanide to the ferric heme of CytC. In contrast, decomposition of the cyanide complex with ferrous CytC, as monitored by magnetic circular dichroism spectroscopy, was slower in mutants compared to WT. Molecular dynamic simulations revealed the increase in the fluctuations of Cα atoms of individual residues of mutant CytC compared to WT, especially in the Ω-loop (70–85), which can cause destabilization of the Fe...S(Met80) coordination link, facilitation of the binding of exogenous ligands cyanide and peroxide, and an increase in peroxidase activity. It was found that only one substitution K72E is enough to induce all these changes, indicating the significance of K72 and the Ω-loop (70–85) for the structure and physiology of mitochondrial CytC. In this work, we also propose using a ferro-ferricyanide buffer as a substrate to monitor the peroxidase activity of CytC. This new approach allows us to determine the rate of peroxidase activity at moderate (200 µM) concentrations of H2O2 and avoid complications of radical formation during the reaction. [ABSTRACT FROM AUTHOR]

Daucosterol (DAU) was isolated from the methanol-chloroform crude extract of six Nepeta species (N. aristata , N. baytopii, N. italica, N. nuda albiflora, N. stenantha and N. trachonitica) using sephadex and silica-gel columns via bioactivity-guided isolation. Spectroscopic methods and comparisons with similar data in the literature determined its structure. DAU was evaluated for enzyme inhibitions, kinetics, DNA protection, and molecular interactions. The inhibition activities of AChE, tyrosinase, BChE, and urease were found to be 21.32±1.24, 3.17±0.45, 16.73±0.10 and 12.95±0.21 μM, respectively. The K i values of the inhibition kinetics of the same enzymes were observed as 0.11, 0.05, 0.12, and 0.12 mM, respectively. DAU exhibited effective protection activity against DNA damage induced by H 2 O 2 and ultraviolet radiation in DNA protection tests. DFT analysis showed low hardness and high softness values. The best binding affinity of DAU was achieved by the enzymes AChE and BChE (for both: −9.90 kcal/mol). As a result of the interaction of standards and DAU with enzymes, it was observed that DAU bound with a higher potential than the standards. Molecular dynamics simulations of these enzymes were examined for 100 ns, and the energy results of the simulation were determined by MM/PBSA calculation in the last 10 ns. Additionally, its pharmacokinetic properties were investigated with SwissADMET, and it was noted that it had low toxic effects and gastrointestinal absorption. Thus, in vitro and in silico analysis determined that the DAU molecule could protect against DNA oxidative damage and an active metabolic enzyme inhibitor. [Display omitted] • Daucosterol was isolated from six different Nepeta species by activity-guided isolation • Daucosterol had potent enzyme inhibition and DNA protection activities • Urease inhibition kinetics and molecular interactions of daucosterol were studied for the first time • Daucosterol exhibited favorable binding constants and affinities with BChE and tyrosinase. [ABSTRACT FROM AUTHOR]

InhA is an enoyl acyl carrier reductase that catalyzes the chemo-selective reduction of its 2-trans-enoyl-ACP substrate. The pharmacological effects of the frontline medications used in the treatment of tuberculosis are elicited by inhibiting the enzyme InhA, which disrupts the mycolic acid biosynthesis pathway. The present study involves development of ligand-based pharmacophore model, docking studies, generation of 3D-QSAR model, and molecular dynamic simulation studies of virtually screened putative InhA inhibitors. The best field-based 3D-QSAR model was validated using partial least-square regression (PLS) method with high regression coefficient for training set (R2) = 0.9256 and test set (R2) = 0.7542, cross-validated coefficient (rcv2) = 0.72 and R2pred = 0.9764. Also, virtual screening yielded compounds 4, 25, 1, and 30 exhibiting appreciable interactions (docking scores −5.972, −3.819, −3.801, and −3.701, respectively with InhA synthetase; PDB ID: 1BVR). Further, ADMET studies supported drug-like potential of compounds 25, 1, and 30 whereas compound 4 showed negligible human oral absorption. The molecular dynamic simulation studies of the top scored molecule 25 suggested stability of 25-1BVR complex over the course of simulation run. Therefore, this work can be helpful for future discovery of novel InhA inhibitors against drug-resistant tuberculosis. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer, one of the most often diagnosed malignancies worldwide, continues to take countless women's lives. Its treatment usually involves targeting the human estrogen receptor alpha (ERα). Current research explores the potential of natural compounds to regulate ERα activity, providing a hopeful direction for breast cancer therapy. Our study utilized a comprehensive approach to identify promising natural compounds for breast cancer treatment, including quantum descriptors, molecular docking, molecular dynamics simulations, and ADMET/pharmacokinetics analysis. Results Six natural compounds derived from podophyllum medicinal plants, namely 4-demethylpodophyllotoxin (NP1), α-peltatin (NP2), podophyllotoxin (NP3), deoxypodophyllotoxin (NP4), podophyllotoxone (NP5), and β-peltatin (NP6), were investigated as potential selective estrogen receptor α (ERα) inhibiting agents for breast cancer. These compounds demonstrated the strongest binding affinity to the target enzyme, with binding energies of − 8.9 and − 8.1 kcal/mol, respectively. Further assessments of drug-likeness and ADME properties were conducted for these compounds, along with quantum calculations (HOMO–LUMO) to evaluate their reactivity. Additionally, molecular dynamics studies were performed to assess the stability of the NP1 and NP2 protein–ligand complexes. Conclusions We analyzed six natural compounds comprehensively, evaluating their ADME properties, molecular docking interactions, quantum descriptors, and dynamic simulations. Our findings demonstrate that these natural compounds are promising possibilities for treating breast cancer. Additionally, they may provide a basis for developing future compounds targeting estrogen receptor α (ERα) activity. Graphical abstract

High-content rubber modified asphalt would let out lots of volatile organic compounds (VOCs), bio-oil was used to reduce the VOCs emission and mixing temperature of high-content rubber modified asphalt. The molecular model of high-content rubber modified bio-asphalt (HRMBA) was built to calculate the solubility parameter, free volume, molecular orientation, and radial distribution function. The effects of bio-oil on the physicochemical properties of HRMBA during VOCs emission process were studied deeply using molecular dynamic simulations and first principles. The differential scanning calorimeter (DSC), Fourier infrared spectrometer (FT-IR), and gel chromatography (GPC) were used to test the glass transition temperature, functional groups, and molecular aggregate and verify the simulated results. The results show that the optimum contents of waste tire in HRMBA is 35%, and bio-oil can promote the compatibility between rubber and asphalt. Free volume of HRMBA shows a strong correlation with the probe Connolly radius, and Connolly radius increases the molecular movements and dissolution of HRMBA. Moreover, the compatibility between bio-oil and rubber are good. Bio-oil can improve the dissolution of rubber into asphalt and inhibit the VOCs emissions of HRMBA. The compatibility between rubber and asphalt are damaged after VOCs emission. A new calculation method was used to evaluate the physicochemical properties of HRMBA, and experiment methods were also used to verify these. [ABSTRACT FROM AUTHOR]

A wide range of bioactive compounds have been created using the versatile pharmacophore pyrimidine. In order to improve biological applications, we, therefore, envisioned adding these privileged moieties. In this work, we developed an efficient 2-aminopyrimidine derivatives. We further investigated the anticancer activity of all the compounds against colon cancer cell lines COLO-205 and HT-29. Out of several compounds synthesized, two compounds SD2 and SD4 have shown comparable potent anticancer activity when compared to standard Cabozantinib. The most potent cytotoxic compound against colon cancer cells in our study was found to be SD2 with an IC50 value of 9.57 μ M. The investigation from molecular docking showed the best binding affinity. The complex stability within an enzyme's pocket was demonstrated by the molecular dynamic simulation running for 100 ns. The work intends to critically search 2-aminopyrimidine derivatives for anticancer activity in two colon cancer cell lines (HT-29 and COLO-205). Advanced computational studies are carried out to provide more insight. Two compounds showed comparative anticancer activity in cytotoxicity and molecular modeling studies with standard. [ABSTRACT FROM AUTHOR]

SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit–protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig_1, Lig_6, and Lig_14 demonstrated binding free energies of −161.49 kJ/mol, −151.28 kJ/mol, and −107.13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of −71.48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer. [ABSTRACT FROM AUTHOR]

Experimental investigation and computational analysis with the DFT approach were done on 4-amino-3-hydroxy naphthalene-1-sulfonic acid (ANSA). Different spectroscopic analyses like NMR, FT-IR, and UV-Visible were performed. The molecular structure was optimized, and the wavenumbers of typical vibrational modes were calculated using the B3LYP method and the 6-311++G (d, p) basis set. After optimization, the calculated bond lengths and bond angles were compared with experimental ones and found well matched, described by RMSD values. Potential energy distribution (PED) obtained by VEDA. 13C and 1H NMR were calculated with the GIAO method which showed great resemblance with the experimental spectra. UV–Vis in different phases were calculated by the TD-DFT method and the CPCM solvent model and compared with the experimental. The HOMO-LUMO energy gap showed a great opportunity for charge transfer inside the molecule. The MEP surface analysis revealed the molecule's charge distribution. To investigate the degree of relative localization of electrons, the FLF diagram was used. Eight distinct receptors were used in biological investigations for molecular docking analysis and a molecular dynamic simulation of 15 ns was performed to determine the best ligand-protein interactions. The drug-likeness was also investigated to see the drug-like properties. [ABSTRACT FROM AUTHOR]

The binding of drugs to plasma proteins determines its fate within the physiological system, hence profound understanding of its interaction within the bloodstream is important to understand its pharmacodynamics and pharmacokinetics and thereby its therapeutic potential. In this regard, our work delineates the mechanism of interaction of Selumetinib (SEL), a potent anti‐cancer drug showing excellent effect against multiple solid tumors, with plasma protein bovine serum albumin (BSA), using methods such as absorption, steady‐state fluorescence, time‐resolved, fluorescence resonance energy transfer, Fourier transform infrared spectra (FTIR), circular dichroism (CD), synchronous and 3D‐fluorescence, salt fluorescence, molecular docking and molecular dynamic simulations. The BSA fluorescence intensity was quenched with increasing concentration of SEL which indicates interactions of SEL with BSA. Stern–Volmer quenching analysis and lifetime studies indicate the involvement of dynamic quenching. However, some contributions from the static quenching mechanism could not be ruled out unambiguously. The association constant was found to be 5.34 × 105 M−1 and it has a single binding site. The Förster distance (r) indicated probable energy transmission between the BSA and SEL. The positive entropy changes and enthalpy change indicate that the main interacting forces are hydrophobic forces, also evidenced by the results of molecular modeling studies. Conformation change in protein framework was revealed from FTIR, synchronous and 3D fluorescence and CD studies. Competitive binding experiments as well as docking studies suggest that SEL attaches itself to site I (subdomain IIA) of BSA where warfarin binds. Molecular dynamic simulations indicate the stability of the SEL–BSA complex. The association energy between BSA and SEL is affected in the presence of different metals differently. [ABSTRACT FROM AUTHOR]

Background. Recombinant plasminogen activator (r-PA) consists of the Kringle-2 and protease domains of human tissue-type plasminogen. It is used clinically to treat coronary artery thrombosis and acute myocardial infarction. However, the expression and production of reteplase (r-PA) are limited due to its susceptibility to proteolysis during manufacturing processes. Therefore, efforts have been made to address this limitation. Materials and methods. To enhance the conformational stability of r-PA and increase its resistance to proteolysis, we used Gly 6 Ala substitutions in the Kringle-2 domain through in silico. We created an in silico mutant collection with eight structures, incorporating four designated mutations (R103S, G39A, G53A, and G55A). Using MODELLER software and homology modeling, we developed three-dimensional structures for two Kringle-2 and tissue plasminogen activator protease domains, including the wild noncleavable form (R103S) and mutants with all four designated mutations. We assessed protein stability using a dynamic cross-correlation matrix by extracting global properties such as Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) from trajectory files. Results. The findings revealed that a single glycine--alanine substitution (G39A) enhanced the conformational stability of r-PA, as evidenced by improvements in RMSD, RMSF, radius of gyration, surface accessibility, hydrogen bond formation, eigenvector projection, and density analysis. Conclusion. The conformational stability of r-PA conferred by glycine replacement with alanine may decrease the propensity for proteolysis in protease -- rich environments across various recombinant systems and potentially enhance its production and expression levels. [ABSTRACT FROM AUTHOR]

Due to the low temperature, the Antarctic marine environment is challenging for protein functioning. Cold‐adapted organisms have evolved proteins endowed with higher flexibility and lower stability in comparison to their thermophilic homologs, resulting in enhanced reaction rates at low temperatures. The Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125) genome is one of the few examples of coexistence of multiple hemoglobin genes encoding, among others, two constitutively transcribed 2/2 hemoglobins (2/2Hbs), also named truncated Hbs (TrHbs), belonging to the Group II (or O), annotated as PSHAa0030 and PSHAa2217. In this work, we describe the ligand binding kinetics and their interrelationship with the dynamical properties of globin Ph‐2/2HbO‐2217 by combining experimental and computational approaches and implementing a new computational method to retrieve information from molecular dynamic trajectories. We show that our approach allows us to identify docking sites within the protein matrix that are potentially able to transiently accommodate ligands and migration pathways connecting them. Consistently with ligand rebinding studies, our modeling suggests that the distal heme pocket is connected to the solvent through a low energy barrier, while inner cavities play only a minor role in modulating rebinding kinetics. [ABSTRACT FROM AUTHOR]

A novel 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4,5-triphenyl-1H-imidazole (DDTI) molecule was synthesised and characterised by FT-IR and NMR (1H and 13C) spectral techniques. The molecular structure was optimised using the density functional theory (DFT) method with B3LYP/6-311 G (d, p) basis set. Natural bonding orbital (NBO) analysis was used to determine the electron densities of donor (i) and acceptor (j) bonds as well as the hyperconjugative interaction energy (E(2)). In highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) calculations, the smaller energy gap value was discovered. Molecular electrostatic potential has been analysed. The Mulliken atomic charges of the carbon, nitrogen and oxygen atoms were calculated at the same level of theory. The dipole moment, polarizability and first-order hyperpolarizability demonstrate the good nonlinear optical (NLO) feature of the title molecule. Molecular docking studies are implemented to analyse the binding energy of the DDTI compound against standard drugs such as the crystal structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with MES, SARS-CoV-2 main protease with an unliganded active site (2019-nCoV, corona virus disease 2019, COVID-19) and the crystal structure of COVID-19 main protease in complex with an inhibitor N3 found to be considered having better antiviral agent. Molecular dynamics simulation was performed for COVID-19 main protease (Mpro: 6WCF/6Y84/6LU7) to understand the elements governing the inhibitory effect and the stability of interactions under dynamic conditions. Virtual ADMET studies were carried out as well and a relationship between biological, electronic and physicochemical qualifications of the target compound was determined. Toxicity prediction by computational technique for the title compound was also carried out. [ABSTRACT FROM AUTHOR]

Introduction: The most common primary brain tumor in adults is glioblastoma multiforme (GBM), accounting for 45.2% of all cases. The characteristics of GBM, a highly aggressive brain tumor, include rapid cell division and a propensity for necrosis. Regretfully, the prognosis is extremely poor, with only 5.5% of patients surviving after diagnosis. Methodology: To eradicate these kinds of complicated diseases, significant focus is placed on developing more effective drugs and pinpointing precise pharmacological targets. Finding appropriate biomarkers for drug discovery entails considering a variety of factors, including illness states, gene expression levels, and interactions between proteins. Using statistical techniques like p-values and false discovery rates, we identified differentially expressed genes (DEGs) as the first step in our research for identifying promising biomarkers in GBM. Of the 132 genes, 13 showed upregulation, and only 29 showed unique downregulation. No statistically significant changes in the expression of the remaining genes were observed. Results: Matrix metallopeptidase 9 (MMP9) had the greatest degree in the hub biomarker gene identification, followed by (periostin (POSTN) at 11 and Hes family BHLH transcription factor 5 (HES5) at 9. The significance of the identification of each hub biomarker gene in the initiation and advancement of glioblastoma multiforme was brought to light by the survival analysis. Many of these genes participate in signaling networks and function in extracellular areas, as demonstrated by the enrichment analysis. We also identified the transcription factors and kinases that control proteins in the proteinprotein interactions (PPIs) of the DEGs. Discussion: We discovered drugs connected to every hub biomarker. It is an appealing therapeutic target for inhibiting MMP9 involved in GBM. Molecular docking investigations indicated that the chosen complexes (carmustine, lomustine, marimastat, and temozolomide) had high binding affinities of -6.3, -7.4, -7.7, and -8.7 kcal/mol, respectively, the mean root-mean-square deviation (RMSD) value for the carmustine complex and marimastat complex was 4.2 Å and 4.9 Å, respectively, and the lomustine and temozolomide complex system showed an average RMSD of 1.2 Å and 1.6 Å, respectively. Additionally, high stability in root-mean-square fluctuation (RMSF) analysis was observed with no structural conformational changes among the atomic molecules. Thus, these in silico investigations develop a new way for experimentalists to target lethal diseases in future. [ABSTRACT FROM AUTHOR]

• In silico screening of 35 phytochemicals from Newbouldia laevis against hexokinase 2. • Insight using molecular docking in terms of binding affinities and interacting residues for predicting molecular mechanism. • Assessing the potency of the lead phytochemicals using molecular dynamic simulations and MMPBSA. • Best drug candidates as hexokinase 2 inhibitors were predicted for further pre-clinical and clinical trials. Newbouldia laevis, also known as the African Border Tree or Fever Tree, is a deciduous tree native to West Africa. The plant is valued for its medicinal properties and is used in traditional medicine for its antimicrobial and anti-inflammatory effects. N. laevis, is a storage tank of phytochemicals with huge health benefits and performances globally for the treatment and management of numerous disease conditions. Limited research exists on the usage of N. laevis for hepatocellular carcinoma (HCC) treatment. This study aims to explore the inhibitory activities of phytochemicals from N. laevis against the hexokinase 2 protein, a target in hepatocarcinoma (HCC) treatment. This study presents a unique in silico approach that includes ligand binding site prediction, molecular docking, molecular dynamics simulation, and Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) methods. A total of 35 phytochemicals with available 3D structures were identified through literature mining. The literature review highlighted the significance of hexokinase 2 protein as a target inhibitor in the treatment of hepatocellular carcinoma (HCC). Molecular docking experiment with the all the identified phytochemicals and hexokinase 2 revealed that all the identified phytochemicals had potential inhibitory activities against the target protein. Moreover, chrysarobin, apigenin and ursolic acid were the best inhibitors with lowest binding energy of −8.9 kcal/mol, −8.7 kcal/mol, and −8.5 kcal/mol, respectively. The docking experiment was validated by comparing the binding affinities with known reference drug Cabozantinib-S-malate (−8.3 kcal/mol). Further, molecular dynamics studies of complexes with the best docking scores and reference drug complexes were described in detail here. The results of 100 ns modeling (RMSD, RMSF, Rg and SASA) show extraordinary stability during the establishment of complexes with apigenin and ursolic acid, as well as favorable binding energy, which was determined theoretically by means of the MM/PBSA method, thereby increase the probability of their acting as promising and likely hexokinase 2 inhibitors. Therefore, the study predicted that apigenin and ursolic acid could be used as a potential inhibitor/antagonist for the hexokinase 2 enzyme. [ABSTRACT FROM AUTHOR]

Graphene membranes of excellent solar absorption and photothermal conversion efficiency have been used in solar-driven water evaporation (SDWE) systems as light-harvesting material. The interfacial evaporation property between graphene membranes and seawater is an important issue to further promote the development of SDWE. In this work, manipulation strategies are presented based on porous structures for tailoring the evaporation performance of graphene membranes. The non-equilibrium molecular dynamic (NEMD) simulation results show that the pore size, pore concentration, and distribution pattern are all key factors in enhancing the evaporation rate. The evaporation performance can achieve the best optimisation when the pore size is 3.1 Å and the pore concentration is the lowest. Moreover, the periodic distribution of porous structures can greatly increase the evaporation rate (about 100 water molecules per nanosecond) due to the improvement of adsorption and desorption balance compared with the random structure. The optimised configuration of the graphene porous used in SDWE systems is proposed, which could increase the evaporation rate to 357.1%. This study could provide some theoretical guidance on graphene membranes for application in both photothermal conversion and solar-driven water purification. [ABSTRACT FROM AUTHOR]

Food preservation is a schematic and scientific procedure employed for the maintenance and improvement of food's quality, shelf life, and nutritional value. Although, on one hand, ancient conventional methods such as freezing, pasteurization, canning, and chemical methods have the potential to lengthen the shelf life of edible substances, but on the other hand, they can deteriorate its nutritional value as well. Present research focuses on the identification of promising bacteriocins against Pseudomonas fragi via subtractive proteomics pipeline as an alternative approach for food preservation. Bacteriocins are small peptides produced by certain microbes to naturally defend themselves by destroying other closely related bacteria residing in their neighborhood. P. fragi lies among the most notable microbes responsible for the elicitation of food spoilage. Due to increasing emergence and prevalence of multidrug resistance bacteria, there is a need to unravel novel drug targets, crucially involved in food decay process. Based on subtractive scrutinization, UDP-N-acetylglucosamine O-acyltransferase (LpxA) was chosen as promising therapeutic protein target that could play a significant role in progression of food spoilage. Subtilosin A, thuricin-CD, and mutacin B-NY266 were found as the most robust inhibitors of LpxA according to the molecular docking assay results. Molecular dynamic simulations and binding energy calculations via MM/PBSA method of LpxA and three top hit docked complexes, i.e., LpxA-subtilosin A, LpxA-thuricin-CD, and LpxA-mutacin B-NY266, revealed stability throughout simulations and ensured that shortlisted bacteriocins had strong affinity for LpxA. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.

Allantoin represents a compound widely employed in pharmaceutical and cosmetic fields. Its safety has been acknowledged by regulatory bodies such as the US Food and Drug Administration, the European Commission for Cosmetics and Consumer and Health and European Directorate for the Quality of Medicines & HealthCare. This justifies its wide use in dermatological/cosmetic formulations and allows their safe use.Allantoin possesses an asymmetric carbon atom, resulting in two enantiomers, with the (S)-enantiomer predominating in plants, although racemization may potentially occur during manufacturing processes. Notably, literature currently lacks enantioselective LC methods for allantoin analysis.In this study, two zwitterionic Cinchona alkaloid-based chiral stationary phases (CSPs), commercially known as CHIRALPAK® ZWIX(+) (CSP1) and CHIRALPAK® ZWIX(-) (CSP2), were utilized for the enantioseparation of allantoin under polar-ionic conditions. By employing a mobile phase consisting of acetonitrile/methanol/water/acetic acid (96:2:2:0.1, v/v/v/v), nearly complete baseline separation (with α=1.08) of allantoin enantiomers was achieved in less than 15 min with both CSPs. Due to the “pseudo-enantiomeric” nature of the two chiral selectors (quinine-based in CSP1 and quinidine-based in CSP2), an inversion of the enantiomer elution order was observed with the two CSPs under identical experimental conditions. Remarkably, this represents a rare instance where these CSPs demonstrate the ability to enantioseparate a non-ionic, non-ionizable species.The application of a molecular dynamics in silico protocol proved useful in elucidating the retention mechanism in depth, casting light on the central role of the H-bond formation and the involvement of the anionic moiety of the CSP 1.

The flavoprotein Cytochrome P450 reductase (CPR) is the unique electron pathway from NADPH to Cytochrome P450 (CYPs). The conformational dynamics of human CPR in solution, which involves transitions from a "locked/closed" to an "unlocked/open" state, is crucial for electron transfer. To date, however, the factors guiding these changes remain unknown. By Site‐Directed Spin Labelling coupled to Electron Paramagnetic Resonance spectroscopy, we have incorporated a non‐canonical amino acid onto the flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) domains of soluble human CPR, and labelled it with a specific nitroxide spin probe. Taking advantage of the endogenous FMN cofactor, we successfully measured for the first time, the distance distribution by DEER between the semiquinone state FMNH• and the nitroxide. The DEER data revealed a salt concentration‐dependent distance distribution, evidence of an "open" CPR conformation at high salt concentrations exceeding previous reports. We also conducted molecular dynamics simulations which unveiled a diverse ensemble of conformations for the "open" semiquinone state of the CPR at high salt concentration. This study unravels the conformational landscape of the one electron reduced state of CPR, which had never been studied before. [ABSTRACT FROM AUTHOR]

α -Glucosidases catalyze the hydrolysis of the α -glucosidic bond located at the non-reducing ends of substrates, resulting in the release of glucose. α -glucosidase is an important drug target for controlling type 2 diabetes. Previous studies have shown that polysaccharide isolated and purified from Camellia oleifera Abel exhibits hypoglycemic properties. In this study, the mode in which the polysaccharide binds and the associated binding free energy, as well as the release mechanism dependent on hydrogen bonding, has been elucidated through the integration of multiple molecular dynamic simulations. Residues Arg200 and Arg400 located at the active site of α -glucosidase play a major role in polysaccharide binding, primarily through electrostatic and hydrogen-bonding interactions. The optimal route for the transportation of polysaccharides has been identified, and a comprehensive analysis of the thermodynamic and kinetic characteristics has been discussed through the application of umbrella sampling techniques. The dynamic delivery properties of α -glucosidase suggest that the energy barrier necessary for the escape of disaccharides is approximately 12 kcal/mol. This barrier primarily arises from the interactions of hydrogen bonding and electrostatic interactions. The results of this study provide a basic understanding of the ligand transport mechanism based on the environment of α -glucosidase, which has practical value for the future design and development of C. oleifera polysaccharides as hypoglycemic drugs. Various molecular dynamics simulation techniques were utilized to investigate the precise binding characteristics and transport mechanism of Camellia oleifera polysaccharides in α-glucosidase. The significance of Arg200 and Arg400 in the stable attachment of Camellia oleifera polysaccharide was recognized, and it was established that electrostatic and hydrogen bonding interactions are pivotal in the binding of polysaccharides. A unique mode of transport for Camellia oleifera polysaccharide, dependent on hydrogen bonding and extensively involving Asp333, was identified. [ABSTRACT FROM AUTHOR]

We report the synthesis, spectroscopic properties, and anti-proliferative efficacy of the adamantane-linked 1,2,4-triazole derivative 5-(adamantan-1-yl)-4-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione. Crystal packing and intermolecular interactions have been quantified using Hirshfeld surfaces and two-dimensional fingerprint plots. ADMET characteristics, bioavailability, and drug-likeness define the compound's bioactivity. The gastrointestinal absorption is anticipated to be high, and the projected bioavailability score is 0.55. The topological polar surface area and iLOGP, XLOGP, WLOGP, and MLOGP lipophilicity parameters have been calculated to be 65.70 Å2, 3.24, 4.74, 5.05, and 4.07, respectively. To investigate 5A4ClT's EGFR inhibition and its use in the treatment of non-small cell lung cancer, Autodock Vina was used to dock it with the crystal structure of the EGFR kinase domain protein. The title chemical hydrophobically interacts with the receptor residues LEU718, VAL726, ALA743, GLU762, THR790, LEU792, MET793, GLY796, ARG841, ASN842, and LEU844 and forms hydrogen bonds with ASP855 and THR854 with an affinity of −8.3 kcal/mol. Toxicity end points and comparison with NSCLC drugs yielded promising findings. 120 ns molecular dynamics simulations confirmed the ligand's dynamic stability in the target protein's binding pocket. This research lays the groundwork for future in vivo investigations of 5A4ClT as a non-small cell lung cancer therapy. [ABSTRACT FROM AUTHOR]

To date, the COVID-19 pandemic has still been infectious around the world, continuously causing social and economic damage on a global scale. One of the most important therapeutic targets for the treatment of COVID-19 is the main protease (Mpro) of SARS-CoV-2. In this study, we combined machine-learning (ML) model with atomistic simulations to computationally search for highly promising SARS-CoV-2 Mpro inhibitors from the representative natural compounds of the National Cancer Institute (NCI) Database. First, the trained ML model was used to scan the library quickly and reliably for possible Mpro inhibitors. The ML output was then confirmed using atomistic simulations integrating molecular docking and molecular dynamic simulations with the linear interaction energy scheme. The results turned out to show that there was evidently good agreement between ML and atomistic simulations. Ten substances were proposed to be able to inhibit SARS-CoV-2 Mpro. Seven of them have high-nanomolar affinity and are very potential inhibitors. The strategy has been proven to be reliable and appropriate for fast prediction of SARS-CoV-2 Mpro inhibitors, benefiting for new emerging SARS-CoV-2 variants in the future accordingly. [ABSTRACT FROM AUTHOR]

We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1–10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests. [ABSTRACT FROM AUTHOR]

Background: The Junín virus (JUNV) is well known for causing argentine haemorrhagic fever (AHF), a severe endemic disease in farming premises. The glycoprotein of JUNV is an important therapeutic target in vaccine design. Despite using drugs and neutralizing weakened antibodies being used in the medication, neither the severity reduced nor eradicated the infection. However, this constraint can be resolved by immunoinformatic approaches. Results: The glycoprotein fasta sequence was retrieved from NCBI to anticipate the B cell and T cell epitopes through the Immune Epitope Database. Furthermore, each epitope underwent validation in Vaxijen 2.0, Aller Top, and Toxin Pred to find antigenic, nonallergic, and non-toxic peptides. Moreover, the vaccine is designed with appropriate adjuvants and linkers. Subsequently, physicochemical properties were determined in ProtParam including solubility and disulphide bonds in the SCRATCH server. The vaccine 3D structure was built using I-TASSER and refined in ModRefine. Docking between JUNV glycoprotein (PDB ID:5NUZ) with a built vaccine revealed a balanced docked complex visualized in the Drug Discovery studio, identified 280 hydrogen bonds between them. The docking score of − 15.5 kcal/mol was determined in the MM/GBSA analysis in HawkDock. MD simulations employed using the GROMACS at 20 ns resulted in minimal deviation and fewer fluctuations, particularly with high hydrogen bond-forming residues. Conclusion: However, these findings present a potential vaccine for developing against JUNV glycoprotein after validating the epitopes and 3D vaccine construct through in silico methods. Therefore, further investigation in the wet laboratory is necessary to confirm the potentiality of the predicted vaccine. [ABSTRACT FROM AUTHOR]

With the increasing environmental requirements for improving products and materials using renewable and sustainable resources, cellulose has been seen as one of the most attractive and promising alternatives to traditional inorganic fillers. We developed a new modification method to improve the interface compatibility between natural rubber and sisal cellulose, to improve the mechanical and thermal conductivity properties of rubber composite. Microcrystalline cellulose (MCC) was extracted from sisal cellulose and then the hydrophobic cellulose (SA‐MCC) was prepared by grafting stearic acid on the surface of MCC. MCC and SA‐MCC were added to the thermal conductivity composite material composed of natural rubber and boron nitride. The results showed that the thermal conductivity and tensile properties of the natural rubber composites increased by 17.3% and 20%, respectively, under the addition of 1.8 wt% SA‐MCC. Furthermore, the interfacial interaction between the components in the composite was studied by molecular dynamics simulation. The solubility parameters, free volume fraction, and molecular binding energy were calculated to verify the effectiveness of the modification. This work is expected to provide a theoretical basis for the design and preparation of high‐performance natural rubber composite materials. Highlights: Cellulose microcrystals were successfully extracted from sisal fiber and modified.Through the combination of boron nitride and the modified cellulose microcrystals, the thermal conductivity and tensile properties of thermal rubber were successfully improved synchronously.A reasonable molecular simulation model was established to analysis the strengthening mechanism from the microscopic point of view.The molecular simulation conclusions on interface enhancement are in good agreement with the experimental properties. [ABSTRACT FROM AUTHOR]

The heterodimeric amino acid transporter systemic XCT plays a crucial role in redox balance regulation by facilitating L-cystine and L-glutamate import/export in a 1:1 ratio. Translating findings from preclinical to clinical contexts poses challenges due to interspecies receptor variations. To understand these differences and achieve success during translating studies, in silico analysis of FDA-approved drugs was performed against three species for systemic XCT receptors with UniProt-ids D4ADU2 (Rattus norvegicus), Q9WTR6 (Mus musculus), and Q9UPY5 (Homo sapiens). Homology modelling produced validated 3D structures for D4ADU2 and Q9WTR6, achieving an excellent model quality score (∼84%). Virtual screening identified common hits in Rat and Mouse Homology Modelled Structures (RHMS and MHMS), including Avodart, Rolapitant, and Olmesartan. In Homo sapiens (PDBs 7P9U and 7P9 V), common hits Dihydroergotamine and Ergotamine showed binding affinities of −12.3 to −10.1 kcal/mol as compared to glutamate and cystine (−4.9 to −5.9 kcal/mol) within the same binding pocket. A 500 ns MD simulation confirmed structural stability, positive correlations and limited atomic displacements. Free energy calculations highlighted the top compounds highly favourable binding affinities across all receptors. These results shed light on structural and dynamical variations among the interspecies receptors-ligands interactions which provide valuable insights into transitioning from preclinical to clinical settings. [ABSTRACT FROM AUTHOR]

This study aims to determine the antibacterial efficacy of a bioactive phytochemical quercetin (QUR), compared to the reference antibiotic ciprofloxacin (CIP), using in vitro and in silico approaches. Following molecular docking, QUR showed strong affinity to the druggable targets from bacteria: Sortase B, Toxic Shock Syndrome Toxin-1, Multidrug Efflux Pump AdeJ and LasR, with binding energies –6.9 to –10.3 kcal/mol. CIP displayed binding energies –7.3 to –7.4 kcal/mol against the target proteins. QUR had stronger efficacy against MEPJ (binding energy: -8.1 kcal/mol) and LasR (binding energy: -10.3 kcal/mol), compared to CIP having binding energies -7.4 and -7.3 kcal/mol, respectively. Molecular dynamics simulation validated the formation of LasR complex with QUR, which was energetically more stable compared to the LasR-CIP complex. Disc diffusion method, using nutrient agar medium, demonstrated antibacterial activity of QUR against both gram-negative (Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus, Streptococcus pneumonia) bacteria with zone diameter of inhibition 10–23 mm and 7–21 mm, respectively. QUR displayed synergistic effect, with growth inhibitory index (GII) values of 0.65–1.15, combined with PIP. QUR-CEF combination displayed synergy against E. coli, P. aeruginosa, and S. pneumoniae with GIIs 0.60–0.73. Pharmacokinetics studies for QUR revealed acceptable parametric values, comparable to that of CIP. Thus, the current integrated in silico and in vitro analysis authenticated QUR as a strong lead molecule to combat bacterial infections, using QUR alone or in combination with conventionally used antibiotics (PIP and CEF). For further validation of our results, clinical experiments are suggested.

Introduction: The most common primary brain tumor in adults is glioblastoma multiforme (GBM), accounting for 45.2% of all cases. The characteristics of GBM, a highly aggressive brain tumor, include rapid cell division and a propensity for necrosis. Regretfully, the prognosis is extremely poor, with only 5.5% of patients surviving after diagnosis.Methodology: To eradicate these kinds of complicated diseases, significant focus is placed on developing more effective drugs and pinpointing precise pharmacological targets. Finding appropriate biomarkers for drug discovery entails considering a variety of factors, including illness states, gene expression levels, and interactions between proteins. Using statistical techniques like p-values and false discovery rates, we identified differentially expressed genes (DEGs) as the first step in our research for identifying promising biomarkers in GBM. Of the 132 genes, 13 showed upregulation, and only 29 showed unique downregulation. No statistically significant changes in the expression of the remaining genes were observed.Results: Matrix metallopeptidase 9 (MMP9) had the greatest degree in the hub biomarker gene identification, followed by (periostin (POSTN) at 11 and Hes family BHLH transcription factor 5 (HES5) at 9. The significance of the identification of each hub biomarker gene in the initiation and advancement of glioblastoma multiforme was brought to light by the survival analysis. Many of these genes participate in signaling networks and function in extracellular areas, as demonstrated by the enrichment analysis.We also identified the transcription factors and kinases that control proteins in the proteinprotein interactions (PPIs) of the DEGs.Discussion: We discovered drugs connected to every hub biomarker. It is an appealing therapeutic target for inhibiting MMP9 involved in GBM. Molecular docking investigations indicated that the chosen complexes (carmustine, lomustine, marimastat, and temozolomide) had high binding affinities of −6.3, −7.4, −7.7, and −8.7 kcal/mol, respectively, the mean root-mean-square deviation (RMSD) value for the carmustine complex and marimastat complex was 4.2 Å and 4.9 Å, respectively, and the lomustine and temozolomide complex system showed an average RMSD of 1.2 Å and 1.6 Å, respectively. Additionally, high stability in root-mean-square fluctuation (RMSF) analysis was observed with no structural conformational changes among the atomic molecules. Thus, these in silico investigations develop a new way for experimentalists to target lethal diseases in future.

BackgroundSoil- and water-transmitted helminths are a major concern in the developing world due to their high prevalence. More than a quarter of the population were estimated to be infected with helminths in these endemic zones.Research designAn in silico approach was used to design a vaccine construct against the Taenia genus utilizing the proteomic information and evaluation of the construct using immune-informatics.ResultsOur study identified 451 conserved proteins in Taenia spp. using the existing proteome; out of these, 141 were found to be expressed in cysticerci. These proteins were screened for antigenic epitopes and a multi-subunit vaccine was constructed. The constructed vaccine was assessed for its efficacy in mounting the appropriate immune response. Our constructed vaccine showed stability and optimal performance against the TLR 4 receptor, which is reported to be upregulated in Taenia infections in hosts.ConclusionImmune-informatics tools help design vaccines for neglected diseases such as those attributed to helminths, which are known to cause widespread morbidity. Our vaccine construct holds tremendous potential in conferring protection against all Taenia spp. of clinical relevance to human.

Abstract Background Single nucleotide polymorphisms (SNPs) have been linked with prostate cancer (PCa) and have shown potential as prognostic markers for advanced stages. Loss of function mutations in PKCι have been linked with increased risk of malignancy by enhancing tumor cell motility and invasion. We have evaluated the impact of two coding region SNPs on the PKCι gene (PRKCI) and their prognostic potential. Methods Genotypic association of non-synonymous PKCι SNPs rs1197750201 and rs1199520604 with PCa was determined through tetra-ARMS PCR. PKCι was docked with interacting partner Par-6 to determine the effect of these variants on PKCι binding capabilities. Molecular dynamic simulations of PKCι docked with Par-6 were performed to determine variant effects on PKCι protein interactions. The possible impact of changes in PKCι protein interactions on epithelial cell polarity was hypothesized. Results PKCι rs1199520604 mutant genotype TT showed association with PCa (p = 0.0055), while rs1197750201 mutant genotype AA also showed significant association with PCa (P = 0.0006). The binding interaction of PKCι with Par-6 was altered for both variants, with changes in Van der Waals energy and electrostatic energy of docked structures. Conclusion Genotypic analysis of two non-synonymous PKCι variants in association with PCa prognosis was performed. Both variants in the PB1 domain showed potential as a prognostic marker for PCa. In silico analysis of the effect of the variants on PKCι protein interactions indicated they may be involved in PCa progression through aberration of epithelial cell polarity pathways.

Abstract Most of the breast cancers are estrogen receptor-positive recurring with a steady rate of up to 20 years dysregulating the normal cell cycle. Dinaciclib is still in clinical trials and considered as a research drug against such cancers targeting CDK2. The major goal of this study was to identify the potential inhibitors of CDK-2 present in Moringa oleifera for treating hormonal receptor positive breast cancers. For this purpose, in silico techniques; molecular docking, MM-GBSA and molecular dynamics simulations were employed to screen Moringa oleifera compounds and their anticancer potential was determined against CDK-2 protein targets. Among 36 compounds of Moringa oleifera reported in literature, chlorogenic acid (1), quercetin (2), ellagic acid (3), niazirin (4), and kaempferol (5) showed good affinity with the target. The interaction of the compounds was visualized using PYMOL software. The profiles of absorption, distribution, metabolism, excretion (ADME) and toxicity were determined using SWISS and ProTox II webservers. The MTT assay was performed in-vitro using MCF-7 cancer cell lines to validate the anticancer potential of Moringa oleifera leaf extract. MTT assay results revealed no significant change in proliferation of Mcf-7 cells following 24 h treatment with fraction A (petroleum ether). However, significant antiproliferative effect was observed at 200 µg/mL dose of fraction B (ethyl acetate) and cell viability was reduced to 40%. In conclusion, the data suggested that all the compounds with highest negative docking score than the reference could be the potential candidates for cyclin dependent kinase-2 (CDK-2) inhibition while ellagic acid, chlorogenic acid and quercetin being the most stable and potent inhibitors to treat estrogen receptor positive breast cancer targeting CDK-2. Moreover, the data suggested that further investigation is required to determine the optimum dose for significant antiproliferative effects using in-vivo models to validate our findings of in-silico analysis.

Abstract In this study, an environmentally friendly, solvent- and catalyst-free synthesis of 2-anilino nicotinic acids derivatives is reported. This operationally simple and green procedure was applied to a selection of primary aromatic amines giving rise to 23 derivatives of 2-anilino nicotinic acids in a very short reaction time (15–120 min) with good to excellent yield. Next, similarity searches were executed on these derivatives to find the possible biological target. These products were screened for inhibition of COX-1 and COX-2 by molecular docking and dynamic studies. In silico studies revealed that among these derivatives, the structure 10 bearing meta-chlorine substitutions could act as COX-1 and COX-2 inhibitors. These results can be used in designing important lead compounds for further development as potential anti-inflammatory drugs.