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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]

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]

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]

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]

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]

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]

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]

• 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]

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]

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 soil bacterium Bacillus subtilis is a model organism to investigate the formation of biofilms, the predominant form of microbial life. The secreted protein BslA self-assembles at the surface of the biofilm to give the B. subtilis biofilm its characteristic hydrophobicity. To understand the mechanism of BslA self-assembly at interfaces, here we built a molecular model based on the previous BslA crystal structure and the crystal structure of the BslA paralogue YweA that we determined. Our analysis revealed two conserved protein-protein interaction interfaces supporting BslA self-assembly into an infinite 2-dimensional lattice that fits previously determined transmission microscopy images. Molecular dynamics simulations and in vitro protein assays further support our model of BslA elastic film formation, while mutagenesis experiments highlight the importance of the identified interactions for biofilm structure. Based on this knowledge, YweA was engineered to form more stable elastic films and rescue biofilm structure in bslA deficient strains. These findings shed light on protein film assembly and will inform the development of BslA technologies which range from surface coatings to emulsions in fast-moving consumer goods. [ABSTRACT FROM AUTHOR]

Fatty acid transport protein 1 (FATP1) is an integral transmembrane protein that is involved in facilitating the translocation of long-chain fatty acids (LCFA) across the plasma membrane, thereby orchestrating the importation of LCFA into the cell. FATP1 also functions as an acyl-CoA ligase, catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and VLCFA (very-long-chain fatty acids) as substrates. It is expressed in various types of tissues and is involved in the regulation of crucial signalling pathways, thus playing a vital role in numerous physiological and pathological conditions. Structural insight about FATP1 is, thus, extremely important for understanding the mechanism of action of this protein and developing efficient treatments against its anomalous expression and dysregulation, which are often associated with pathological conditions such as breast cancer. As of now, there has been no prior prediction or evaluation of the 3D configuration of the human FATP1 protein, hindering a comprehensive understanding of the distinct functional roles of its individual domains. In our pursuit to unravel the structure of the most commonly expressed isoforms of FATP1, we employed the cutting-edge ALPHAFOLD 2 model for an initial prediction of the entire protein's structure. This prediction was complemented by molecular dynamics simulations, focusing on the most promising model. We predicted the structure of FATP1 in silico and thoroughly refined and validated it using coarse and molecular dynamics in the absence of the complete crystal structure. Their relative dynamics revealed the different properties of the characteristic FATP1. [ABSTRACT FROM AUTHOR]

RuBisCO is the main photosynthetic enzyme of carbon assimilatory pathways in nature. Despite being the most abundant protein on earth, RuBisCO is still relatively underutilised in the food chain. Although there are sequence and structure details in the database, there are few instances of studies on evolutionary relationships. A bioinformatics and in silico study was conducted to check sequence and structural differences of RuBisCO among different photosynthetic organisms. RuBisCO from Oryza sativa showed an abundance of charged amino acids, salt-bridges, and intra-protein interactions and was more hydrophilic in nature compared to Nostoc sp., Chlamydomonas reinhardtii, and Nicotiana tabacum. From molecular dynamics simulations, lower root mean square deviation and root mean square fluctuation indicate that RuBisCO from Oryza sativa was more stable, followed by Nicotiana tabacum, and a lower radius of gyrations indicates their tight packing. From this study, it was clear that some specific evolutions in charged amino acids of RuBisCO of monocot, i.e., Oryza sativa, make it more stable and stronger than other plant groups. The study concludes that a more stable nature of RuBisCO is gained from monocot Oryza sativa. [ABSTRACT FROM AUTHOR]

Many endothermic liquid–liquid transitions, occurring at a temperature Tn+ above the melting temperature Tm, are related to previous exothermic transitions, occurring at a temperature Tx after glass formation below Tg, with or without attached crystallization and predicted by the nonclassical homogenous nucleation equation. A new thermodynamic phase composed of broken bonds (configurons), driven by percolation thresholds, varying from ~0.145 to Δε, is formed at Tx, with a constant enthalpy up to Tn+. The liquid fraction Δε is a liquid glass up to Tn+. The solid phase contains glass and crystals. Molecular dynamics simulations are used to induce, in NiTi2, a reversible first-order transition by varying the temperature between 300 and 1000 K under a pressure of 1000 GPa. Cooling to 300 K, without applied pressure, shows the liquid glass presence with Δε = 0.22335 as memory effect and Tn+ = 2120 K for Tm = 1257 K. [ABSTRACT FROM AUTHOR]

Using molecular dynamics simulations, the mechanical behavior of the N i / N i 3 A l - γ / γ ′ system has been studied by performing tensile and compression tests at room and high temperature. Before loading tests, the N i / N i 3 A l - γ / γ ′ system is first thermally relaxed. This relaxation step leads to the formation of misfit dislocations resulting from the difference between the lattice parameters of the γ and γ ′ phases. Simulation tests show that when the temperature increases, there is a decrease in the elastic modulus and the yield stress of the system whatever the loading direction. This is due to the increase of the dislocations density. Depending on the loading direction, our simulations reveal a tension/compression asymmetry which decreases with increasing temperature. This behavior is discussed by taking into account the dislocations ability to glide according to the difference of properties between phases depending on the loading direction and the evolution of the γ / γ ′ lattice misfit as a function of the temperature. [ABSTRACT FROM AUTHOR]

Diabetes mellitus significantly contributes to breast cancer progression, where hyperglycemia upregulates specific genes, leading to more aggressive tumor growth. In patients with BC that develop diabetes, neuregulin 1 (NRG1) and epidermal growth factor receptor 3 (ERBB3) overexpression exacerbate tumor growth and progression. Since the interaction between NRG1 and ERBB3 is critical for tumor growth, understanding the molecular mechanisms underlying NRG1–ERBB3 complex formation is essential for elucidating diabetes-assisted breast cancer progression. However, the key residues forming the NRG1–ERBB3 complex remain unknown. Here, we substituted specific residues in NRG1 with alanine and studied its interactions with ERBB3 using computational structural biology tools. We further screened the South African natural compounds database to target the complex's interface residues to discover potential inhibitors. The conformational stability and dynamic features of NRG1–WT, –H2A, –L3A, and –K35A complexed with ERBB3 were subjected to 400 ns molecular dynamics simulations. The free binding energies of all NRG1–ERBB3 complexes were calculated using the molecular mechanics-generalized Born surface area (MM/GBSA). The H2 and L3 alanine substitutions caused a loss of interaction with ERBB3 residue D73, weakening the interaction with ERBB3. Screening 1300 natural compounds identified four (SANC00643, SANC00824, SANC00975, and SANC00335) with the best potential to inhibit ERRB3-NRG1 coupling. The binding free energies for each complex were − 48.55 kcal/mol for SANC00643, − 47.68 kcal/mol for SANC00824, − 46.04 kcal/mol for SANC00975, and − 45.29 kcal/mol for SANC00335, showing their overall stronger binding with ERBB3 than NRG1 and their potential to act as ERBB3-NRG1 complex inhibitors. In conclusion, this complex may represent a residue-specific drug target to inhibit BC progression. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 virus is the causative agent of COVID-19 still pose significant threat to humanity. Discovery of an effective medication regime against this infection still under development. In the present study the potentiality of selected naturally occurring compounds as a SARS-CoV-2 MPro binder were investigated employing molecular docking and dynamics simulation. The Quantum chemical calculations were used to optimize the 3 D geometry of hits. Known inhibitor profiles were used for comparison purposes. The values of Binding Energy showed that the majority of natural ligands have better affinity to MPro, compared to drugs used to cure SARS-CoV-2. The biological and pharmacological properties of these ligands were on the same side as the docking and molecular dynamic results. [ABSTRACT FROM AUTHOR]

The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib's downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of −41.48 and −29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of −37.92 and −38.5 kJ/mol against ERBB and −41.2 and −46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies. [ABSTRACT FROM AUTHOR]

Linear alkanes (n‐alkanes) are chemically the most simple linear hydrophobic molecules in nature. Studying the incorporation of n‐alkanes into lipid membranes is therefore a good starting point toward understanding the behavior of hydrophobic molecules in lipid membranes and to assess how accurately molecular dynamics models describe such systems. Here, the miscibility and structure of different n‐alkanes—n‐decane (C10), n‐eicosane (C20), and n‐triacontane (C30)—in dipalmitoylphosphatidylcholine membranes are investigated using two of the most used force fields for lipid membrane molecular dynamics simulations (CHARMM36 and Slipids). The n‐alkanes are miscible in the membrane up to a critical volume fraction, ϕc, that depends on the force field interaction parameters used. ϕc is dependent on alkane chain length only for the model with more disordered chains (Slipids). Below ϕc, a comparison with 2H nuclear magnetic resonance (NMR) spectra indicates that a more realistic structure of the longer alkane molecules (C20 and C30) is obtained using the Slipids force field. On the other hand, for the shorter alkane (C10), Slipids simulations underestimate molecular order and CHARMM36 simulations enable a precise prediction of its experimental spectrum. The predicted 2H NMR spectra are highly sensitive to 1–4 electrostatic interactions, and suggest that a reduction of the partial charges of the longer alkanes and acyl chains in CHARMM36 results in a better performance. The results presented indicate that lipid membranes with incorporated alkanes are highly valuable systems for the validation of force fields designed to perform lipid membrane simulations. [ABSTRACT FROM AUTHOR]

Magnaporthe oryzae is the causal agent of rice blast, and understanding how abiotic stress affects the resistance of plants to this disease is useful for designing disease control strategies. In this paper, the effects of temperature and microwave irradiation on the effector complex comprising APikL2A from M. oryzae and sHMA25 from foxtail millet were investigated by molecular dynamics simulations using the GROMACS software package. While the structure of APikL2A/sHMA25 remained relatively stable in a temperature range of 290 K (16.85 °C) to 320 K (46.85 °C), the concave shape of the temperature-dependent binding free energy curve indicated that there was maximum binding affinity between APikL2A and sHMA25 at 300 K–310 K. This coincided with the optimum infectivity temperature, thus suggesting that coupling of the two polypeptides may play a role in the infection process. A strong oscillating electric field destroyed the structure of APikL2A/sHMA25, although it was stable and not susceptible to weak electric fields. [ABSTRACT FROM AUTHOR]

Protein kinase p38γ is an attractive target against cancer because it plays a pivotal role in cancer cell proliferation by phosphorylating the retinoblastoma tumour suppressor protein. Therefore, inhibition of p38γ with active small molecules represents an attractive alternative for developing anti-cancer drugs. In this work, we present a rigorous and systematic virtual screening framework to identify potential p38γ inhibitors against cancer. We combined the use of machine learning-based quantitative structure activity relationship modelling with conventional computer-aided drug discovery techniques, namely molecular docking and ligand-based methods, to identify potential p38γ inhibitors. The hit compounds were filtered using negative design techniques and then assessed for their binding stability with p38γ through molecular dynamics simulations. To this end, we identified a promising compound that inhibits p38γ activity at nanomolar concentrations and hepatocellular carcinoma cell growth in vitro in the low micromolar range. This hit compound could serve as a potential scaffold for further development of a potent p38γ inhibitor against cancer. [ABSTRACT FROM AUTHOR]

Metal–organic frameworks (MOFs) are porous material formed by the self‐assembly of metallic ligands and organic linkers. They are a good candidate for CO2 gas capture because they have large surface areas and the metal or linker can be tuned to improve CO2 uptake. In the quest for water and acid stable MOFs, a phosphonate‐based organic linker has recently been designed by Glavinovic et al. (Chem. Eur. J. 2022, 28, e202200874). By combining ionic calcium nodes, water and methanol molecules, they formed a microporous network, CALF‐37. This network has been shown to be robust and can maintain its pore shape even in absence of water molecules or by the inclusion of gas molecules, such as CO2. The network can be heated to release the water and methanol molecules and form a dehydrated MOF, which retains its shape with the imprinted pore within. Herein, we perform molecular dynamics (MD) simulations in order to provide insight into the CO2 capture and sequestration ability of the CALF‐37. We model the dehydration of the inactivated MOF (HCALF‐37) in the absence and in the presence of methanol molecules by progressively withdrawing water molecules from the MOF networks. We determine the crystal structure of the intermediate states from HCALF‐37 to CALF‐37 and shed light on the critical role of water molecules in the mediation of metal‐linker bonds. Our calculations also reveal that the favorable interactions between the CO2 molecules and the aromatic core of the linkers and metallic ions are responsible for the efficient sequestration of the gas in the CALF‐37. [ABSTRACT FROM AUTHOR]

Candida dubliniensis is an opportunistic pathogen associated with oral and invasive fungal infections in immune-compromised individuals. Furthermore, the emergence of C. dubliniensis antifungal drug resistance could exacerbate its treatment. Hence, in this study a multi-epitope vaccine candidate has been designed using an immunoinformatics approach by targeting C. dubliniensis secreted aspartyl proteinases (SAP) proteins. In silico tools have been utilized to predict epitopes and determine their allergic potential, antigenic potential, toxicity, and potential to elicit interleukin-2 (IL2), interleukin-4 (IL4), and IFN-γ. Using the computational tools, eight epitopes have been predicted that were then linked with adjuvants for final vaccine candidate development. Computational immune simulation has depicted that the immunogen designed emerges as a strong immunogenic candidate for a vaccine. Further, molecular docking and molecular dynamics simulation analyses revealed stable interactions between the vaccine candidate and the human toll-like receptor 5 (TLR5). Finally, immune simulations corroborated the promising candidature of the designed vaccine, thus calling for further in vivo investigation. [ABSTRACT FROM AUTHOR]

The current pandemic Covid-19 brought about by a newly emerged and highly infectious virus named as Sars-CoV-2 as a worldwide danger, has infected more than 600 million people and number of deaths are continuously rising day by day. Till date there are no medications accessible for treatment. All over the world scientists and researchers are involved in the study of this emerged virus and its lifecycle. Structures of proteins in the life cycle of virus has been revealed in RCSB PDB (Research Collaboratory for Structural Bioinformatics Protein Data Bank) by researchers. Citrus fruits are used to treat many distresses of humans. Literature survey shows that it has various activities. Our research work is meant to identify the phytoconstituents which are having phenolic composition and good antiviral and antioxidant properties from citrus fruits against Covid-19 proteins (spike binding domain with ACE2 receptor and spike binding domain with Main protease) and to know its in-silico molecular basis. In this study, about 25 compounds from citrus fruits which is having a good antiviral and antioxidant properties and also phenolic composition were employed for molecular docking analysis, molecular dynamic simulation studies and ADME studies. Based on present study 2 compounds from Citrus fruits acted well against the Covid-19 proteins. The MD simulations were employed to identify Hesperidin and Procyanidin B2 as hit compounds. Further ADME analysis were studied for top 2 compounds, these compounds can be further taken for in-vitro studies to know the effective activity against Covid-19. [ABSTRACT FROM AUTHOR]

Unraveling the intricacies of β-glucuronidase inhibition is pivotal for developing effective strategies in applications specific to gastrointestinal health and drug metabolism. Our study investigated the efficacy of some Hibiscus trionum phytochemicals as β-glucuronidase inhibitors. The results showed that cleomiscosin A and mansonone H emerged as the most potent inhibitors, with IC 50 values of 3.97 ± 0.35 μM and 10.32 ± 1.85 μM, respectively. Mechanistic analysis of β-glucuronidase inhibition indicated that cleomiscosin A and the reference drug EGCG displayed a mixed inhibition mode against β-glucuronidase, while mansonone H exhibited noncompetitive inhibition against β-glucuronidase. Docking studies revealed that cleomiscosin A and mansonone H exhibited the lowest binding affinities, occupying the same site as EGCG, and engaged significant key residues in their binding mechanisms. Using a 30 ns molecular dynamics (MD) simulation, we explored the interaction dynamics of isolated compounds with β-glucuronidase. Analysis of various MD parameters showed that cleomiscosin A and mansonone H exhibited consistent trajectories and significant energy stabilization with β-glucuronidase. These computational insights complemented experimental findings, underscoring the potential of cleomiscosin A and mansonone H as β-glucuronidase inhibitors. [Display omitted] • Four coumarins and a xanthone were isolated from Hibiscus trionum. • Cleomiscosin A and mansonone H displayed the lowest IC 50. • Cleomiscosin A displayed a mixed inhibition mode. • Mansonone H depicted a noncompetitive inhibition mechanism. • The outputs of in silico analyses are in line with the results of in vitro assays. [ABSTRACT FROM AUTHOR]

• Three new and one known guaiane-type sesquiterpenoids were isolated from C.migao. • The new compounds were named as (cinmganoid D − F). • Endogenous antioxidant enzymes analysis of these compounds were tested against CAT, SOD, POD, and Nrf-2. • The compounds were evaluated for their anti-inflammatory activities against NO production and pro-inflammatory cytokines. • In silico molecular docking and molecular dynamic simulations studies were also directed. Inflammatory processes are renowned as the fundamental basis for numerous pathological conditions. The objective of this study was to assess the antioxidant, anti-inflammatory, molecular docking, and molecular dynamics simulation properties of 3 previously undescribed and 1 known guaiane-type sesquiterpenoids isolated from Cinnamomum migao. The structures of these compounds were confirmed using numerous chromatographic and spectroscopic methods, such as high-resolution electrospray ionization mass spectrometry (HRESIMS), one-dimensional nuclear magnetic resonance (1D NMR), two-dimensional nuclear magnetic resonance (2D NMR), and experimental circular dichroism (ECD). Additionally, in oxidatively stressed mouse hepatocytes, all tested compounds at a concentration of 50 µM increased the levels of natural antioxidant enzymes such as CAT, SOD, POD, and Nrf-2 compared to those in untreated cells. Compounds 1 and 2 strongly suppressed NO generation and proinflammatory cytokine production, with IC 50 values of 8.76 and 5.45 µM, respectively, against TNF-α mRNA. Furthermore, the molecular docking and simulations explore the high affinity of the selected compounds and best fit in the TNF-α active site. Compounds 1 and 2 show prominent binding energies and bring significant confirmational changes in the TNF-α protein. The results of this study provide further validation for the traditional use of C. migao in the treatment of inflammation and pain, providing novel evidence regarding the therapeutic potential of the identified guaiane-type sesquiterpenoids. [Display omitted] [ABSTRACT FROM AUTHOR]

• Partial virus-like particle models were constructed for chimeric vaccine simulations. • MIR-inserted sequence properties have a greater impact on HBc self-assembly than its length. • MD simulation well predicts the surface hydrophobicity and overall stability of HBc-based vaccines. • MD simulation minimizes design failures and provides guidance for the downstream processing of chimeric VLP vaccines. Self-assembling virus-like particles (VLPs) are promising platforms for vaccine development. However, the unpredictability of the physical properties, such as self-assembly capability, hydrophobicity, and overall stability in engineered protein particles fused with antigens, presents substantial challenges in their downstream processing. We envision that these challenges can be addressed by combining more precise computer-aided molecular dynamics (MD) simulations with experimental studies on the modified products, with more to-date forcefield descriptions and larger models closely resembling real assemblies, realized by rapid advancement in computing technology. In this study, three chimeric designs based on the hepatitis B core (HBc) protein as model vaccine candidates were constructed to study and compare the influence of inserted epitopes as well as insertion strategy on HBc modifications. Large partial VLP models containing 17 chains for the HBc chimeric model vaccines were constructed based on the wild-type (wt) HBc assembly template. The findings from our simulation analysis have demonstrated good consistency with experimental results, pertaining to the surface hydrophobicity and overall stability of the chimeric vaccine candidates. Furthermore, the different impact of foreign antigen insertions on the HBc scaffold was investigated through simulations. It was found that separately inserting two epitopes into the HBc platform at the N-terminal and the major immunogenic regions (MIR) yields better results compared to a serial insertion at MIR in terms of protein structural stability. This study substantiates that an MD-guided design approach can facilitate vaccine development and improve its manufacturing efficiency by predicting products with extreme surface hydrophobicity or structural instability. [ABSTRACT FROM AUTHOR]

[Display omitted] • The interface and transfer properties of DCM captured by ILs are systematically studied. • The K L a o of DCM in [P 4444 ][C 5 COO] is determined to be 1.86 × 10−3 to 4.27 × 10−3/s from 20 to 35 °C. • The tilt angle of [C 5 COO]− with respect to the interface was within the range of 37° < θ′ < 70°. • The carboxyl group of anions and the H atoms of DCM are oriented to the liquid phase at the interface. • MD simulation provides insights into the properties of absorption and desorption processes. In this study, a strategy for dichloromethane (DCM) capture using ionic liquids (ILs) was systematically investigated from the perspective of dynamic analysis. The diffusion coefficient, Henry's law constant (H), saturated absorption capacity, and overall volumetric liquid-side mass-transfer coefficient (K L a o) of four types of ILs were obtained. Among all the ILs studied, tetrabutylphosphonium caproate ([P 4444 ][C 5 COO]) demonstrated superior DCM absorption capabilities, and its corresponding H value (3.13 Pa m3/mol at 25 °C) was markedly lower than those of solvents documented in the literature. Furthermore, its K L a o value was determined to be 2.77 × 10−3/s at 25 °C, which was measured in a customized cylindrical absorption bottle with a height of 150 mm and an inner diameter of 16 mm. The absorption bottle, fitted with a gas inlet tube having an inner diameter of 5 mm and positioned 5 mm above its base, utilized a simple bubbling technique to introduce gas into the liquid phase, eliminating the need for gas-dispersion equipment. Nevertheless, ILs with high affinities showed relatively high initial mass-transfer rates for DCM. Based on molecular dynamics (MD) simulations, the vapor–liquid interface properties, including mass and number density profiles, molecular orientation, and surface tension, were investigated. This revealed that in the pure [P 4444 ][C 5 COO] system, the alkyl chain of the anion was oriented toward the gas phase, while the carboxyl group was oriented toward the bulk. The tilt angle of [C 5 COO]− with respect to the interface was within the range of 37° < θ′ < 70°. For the [P 4444 ][C 5 COO]/DCM mixture, at the interface, the anion exhibits an enhanced ordered orientation, while the cation shows a more disordered orientation. [ABSTRACT FROM AUTHOR]

The main cysteine protease (Mpro) of coronavirus SARS-CoV-2 has become a promising target for computational development in anti-COVID-19 treatments. Here, we benchmarked the performance of six biomolecular molecular dynamics (MD) force fields (OPLS-AA, CHARMM27, CHARMM36, AMBER03, AMBER14SB and GROMOS G54A7) and three water models (TIP3P, TIP4P and SPC) for reproducing the native fold and the enzymatic activity of Mpro as monomeric and dimeric units. The MD sampling up to 1 μs suggested that the proper choice of the force fields and water models plays an essential role in reproducing the tertiary structure and the inter-residue distance between the catalytic dyad His41-Cys145. We found that while most benchmarked all-atom force fields reproduce well the native fold of Mpro, the CHARMM27/TIP3P and OPLS-AA/TIP4P setups revealed a good performance in reproducing the structure of the catalytic domain. In addition, these FF setups were also well-adopted for MD sampling of Mpro at the physiologic conditions by mimicking the presence of 100 mM NaCl and the elevated temperature of 310 K. Finally, both FFs were also performed well in reproducing the native fold of Mpro in a dimeric form. Therefore, comparing the preservation of the native fold of Mpro and the stability of its catalytic site architecture, our MD benchmarking suggests that the OPLS-AA/TIP4P and CHARMM27/TIP3P MD setups at the physiologic conditions may be well-suited for rapid in silico screening and developing broad-spectrum anti-coronaviral therapeutic agents. [Display omitted] • The main cysteine protease (Mpro) of coronavirus SARS-CoV-2 is a promising target. • Benchmarking six MD force fields, such as (OPLS-AA, CHARMM27, CHARMM36, AMBER03, AMBER14SB and GROMOS G54A7, is performed. • Native fold of monomeric and dimeric Mpro is considered. • Tertiary structure and the inter-residue distance between the catalytic dyad His41-Cys145 as key parameters. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes are a virulence factor in many Gram-positive organisms. The specific activity of the Bacillus thuringiensis PI-PLC is significantly increased by adding phosphatidylcholine (PC) to vesicles composed of the substrate phosphatidylinositol, in part because the inclusion of PC reduces the apparent Kd for the vesicle binding by as much as 1000-fold when comparing PC-rich vesicles to PI vesicles. This review summarizes (i) the experimental work that localized a site on BtPI-PLC where PC is bound as a PC choline cation—Tyr-π complex and (ii) the computational work (including all-atom molecular dynamics simulations) that refined the original complex and found a second persistent PC cation—Tyr-π complex. Both complexes are critical for vesicle binding. These results have led to a model for PC functioning as an allosteric effector of the enzyme by altering the protein dynamics and stabilizing an 'open' active site conformation. [ABSTRACT FROM AUTHOR]

Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural population analysis (NPA) charges, frontier molecular orbitals, molecular electrostatic potentials, and the chemical reactivity descriptors for EVO and RUT were also investigated. Furthermore, molecular docking, molecular dynamics simulations, and the analysis of the binding free energies of EVO and RUT were carried out against the anticancer target topoisomerase 1 (TOP1) to clarify their anticancer mechanisms. The docking results indicated that they could inhibit TOP1 by intercalating into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, suggesting that they may be potential TOP1 inhibitors. Molecular dynamics (MD) simulations evaluated the binding stability of the TOP1–DNA–ligand ternary complex. The calculation of binding free energy showed that the binding ability of EVO with TOP1 was stronger than that of RUT. These results elucidated the structure–activity relationship and the antitumor mechanism of EVO and RUT at the molecular level. It is suggested that EVO and RUT may be potential compounds for the development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

Aim and Background: Mycobacterium tuberculosis (TB) remains the leading cause of human death posing one of the most serious threats to public health around the world. New strategies need to be developed to combat the growing danger by multidrug resistance. The present study aims to screen three different compounds inhibiting the binding pocket of Regulatory Repressor Protein EthR of Mycobacterium tuberculosis. In this study we performed pharmacophore modeling based virtual screening to identify the potential inhibitors against EthR of Mycobacterium tuberculosis. Based on the binding energy and hydrogen bond interactions three compounds were selected as potential inhibitors. Materials and Methods: Structure of EthR protein (PDB ID: 5NZ0) was retrieved from pdb databank. Further, we retrieved ligands from ZINC database (ZINC223412753, ZINC030691754, ZINC170602403). Next, Computational screening, Docking studies and Molecular dynamic simulations were performed to validate the stability of the complexes. Results: The molecular docking showed that all ligands interact with EthR protein of Mycobacteriam. Further, molecular dynamics simulation showed that ligand ZINC223412753 form comparatively more stable complex with EthR. Results showed that all the three ligands could be a potential inhibitor of EthR. Conclusion: These compounds can serve as a starting point in rational design of selective potent inhibitors against Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

Mycoplasma genitalium, besides urethritis, causes a number of other sexually transmitted diseases, posing a significant health threat to both men and women, particularly in developing countries. In light of the rapid appearance of multidrug-resistant strains, M. genitalium is regarded as an emerging threat and has been placed on the CDC's "watch list". Hence, a protective vaccine is essential for combating this pathogen. In this study, we utilized reverse vaccinology to develop a chimeric vaccine against M. genitalium by identifying vaccine targets from the reference proteome (Strain G-37) of this pathogen. A multiepitope vaccine was developed using proteins that are non-toxic, non-allergic, and non-homologous to human proteins. Several bioinformatic tools identified linear and non-linear B-cell epitopes, as well as MHC epitopes belonging to classes I and II, from the putative vaccine target proteins. The epitopes that showed promiscuity among the various servers were shortlisted and subsequently selected for further investigation based on an immunoinformatic analysis. Using GPGPG, AAY, and KK linkers, the shortlisted epitope sequences were assembled to create a chimeric construct. A GPI anchor protein immunomodulating adjuvant was adjoined to the vaccine construct's N-terminus through the EAAK linker so as to improve the overall immunogenicity. For further investigations of the designed construct, various bioinformatic tools were employed to study the physicochemical properties, immune profile, solubility, and allergenicity profile. A tertiary chimeric design was computationally modeled using I-TASSER and Robetta and was subsequently refined through GalaxyRefine. ProSA-Web was exploited to corroborate the quality of the construct by detecting errors and the Ramachandran plot was used to identify possible quality issues. Simulation studies of the molecular dynamics demonstrated the robustness and flexibility of the designed construct. Following the successful docking of the designed model to the immune receptors, the construct was computationally cloned into Escherichia coli plasmids to affirm the efficient expression of the designed construct in a biological system. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins—papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)—in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors. Ouabain was suggested to act as a dual inhibitor for both PLpro and Mpro enzymes, while Digitoxin bonded perfectly to RdRp. In addition, Salinomycin targeted PLpro. Particularly, Niclosamide was found to target AAK1 with greater affinity compared to the reference drug. Our study provides comprehensive molecular-level insights for identifying or designing novel anti-COVID-19 drugs. [ABSTRACT FROM AUTHOR]

Nicotinamide is a high‐value chemical that has been widely applied in various aspects of daily life. Nitrile hydratase (NHase) is capable of carrying out biotransformation of nitriles to amides and has shown great potential in the green synthesis of nicotinamide. The high‐molecular mass NHase (H‐NHase) from Rhodococcus rhodochrous J1 has been applied in the industrial‐scale production of acrylamide; however, its activity is not ideal towards aromatic 3‐cyanopyridines, resulting in its substrate preference towards aliphatic nitriles. In this study, a hinge residue at the entrance of the substrate access tunnel of H‐NHase was identified through substrate access tunnel calculations, site‐saturation mutagenesis, molecular docking and molecular dynamics simulations. The corresponding mutant βW48Y showed a 5.9‐fold higher specific activity towards 3‐cyanopyridine than that of its parental enzyme, with better thermostability, proving itself to be a competitive candidate for the industrial production of nicotinamide. [ABSTRACT FROM AUTHOR]

This research investigates antiviral potential of extracted honeybee products against COVID-19 main protease (Mpro) by computational methods. The crystal structure of COVID-19 Mpro was obtained from the protein data bank. Six synthetic drugs with antiviral properties were used as control samples in order to compare the results with those of natural ligands. The six honeybee components, namely 3,4,5-Tricaffeoylquinic acid, Kaempferol-3-O-glucoside, (E)-2′-Geranyl-3′,4′,7-Trihydroxyflavanone, 6-Cinnamylchrysin, (+)-Pinoresinol, and (24E)-3-Oxo-27,28-dihydroxycycloart-24-en-26-oic acid, have represented the lowest binding energies of −9.0, −8.5, −8.2, −7.8, −7.7, −7.3 and −6.7 Kcal/mol, respectively. These natural inhibitors were then picked for further investigations on their pharmacokinetic features. Also a 150 ns of Molecular dynamics simulations were carried out in order to evaluate their effects on protein structure and dynamics. The 3, 4, 5-Tricaffeoylquinic acid is hopefully proposed for COVID-19 Mpro inhibition if further in vitro, in vivo, and clinical trial studies will approve its effectiveness against COVID-19. [ABSTRACT FROM AUTHOR]

Herein, the curing kinetics and the glass transition temperature (Tg) of MXene/phenolic epoxy composites with two curing agents, i.e., 4,4-diaminodiphenyl sulfone (DDS) and dicyandiamine (DICY), are systematically investigated using experimental characterization, mathematical modeling and molecular dynamics simulations. The effect of MXene content on an epoxy resin/amine curing agent system is also studied. These results reveal that the MXene/epoxy composites with both curing agent systems conform to the SB(m,n) two-parameter autocatalytic model. The addition of MXene accelerated the curing of the epoxy composite and increased the Tg by about 20 K. In addition, molecular dynamics were used to simulate the Tg of the cross-linked MXene/epoxy composites and to analyze microstructural features such as the free volume fraction (FFV). The simulation results show that the introduction of MXene improves the Tg and FFV of the simulated system. This is because the introduction of MXene restricts the movement of the epoxy/curing agent system. The conclusions are in good agreement with the experimental results. [ABSTRACT FROM AUTHOR]

MEL-type zeolite was selected as a typical porous material to theoretically capture the purification scenario of a model landfill leachate comprising PbCl2 and CuCl2 varying the pressure (2.4–48 MPa). Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) was applied to simulate the equilibrium state (0.5 ns) and dynamics of Pb2+, Cu2+ and Cl− and water molecules (4 ns). Overall, the flux through the MEL membrane was increased by the increase of pressure. Lennard-Jones potential was used to explain non-bonded interactions between the membrane and ions as well as water molecules, in terms of values of energy and snapshots were taken from the evolution of purification phenomenon. The molecular patterns of accumulation of ions in the vicinity of zeolitic membrane were also captured as functions of the energies of the interaction between the contaminants and porous membrane. Mean square displacement (MSD) variation was indicative of the effect of pressure on dynamics of heavy metal separation; higher energies obtained at higher pressures, as reflected in alteration of van der Waals (vdW) force between ions and water molecules. The membrane revealed rejection above 70% for Pb2+, and almost 100% against Cu2+ and Cl−, respectively. Density of water remained almost 1 g cm3, but depending on population of water molecules decreased after passage into the zeolite membrane. [ABSTRACT FROM AUTHOR]

Innovations in computer hardware and software capabilities have paved the way for advances in molecular modelling techniques and methods, leading to an unprecedented expansion of their potential applications. In contrast to the docking technique, which usually identifies the most stable selector-selectand (SO-SA) complex for each enantiomer, the molecular dynamics (MD) technique enables the consideration of a distribution of the SO-SA complexes based on their energy profile. This approach provides a more truthful representation of the processes occurring within the column. However, benchmark procedures and focused guidelines for computational treatment of enantioselectivity at the molecular level are still missing. Twenty-eight molecular dynamics simulations were performed to study the enantiorecognition mechanisms of seven N -3,5-dinitrobenzoylated α- and β-amino acids (DNB-AAs), occurring with the two quinine- and quinidine-based (QN-AX and QD-AX) chiral stationary phases (CSPs), under polar-ionic conditions. The MD protocol was optimized in terms of box size, simulation run time, and frame recording frequency. Subsequently, all the trajectories were analyzed by calculating both the type and amount of the interactions engaged by the selectands (SAs) with the two chiral selectors (SOs), as well as the conformational and interaction energy profiles of the formed SA-SO associates. All the MDs were in strict agreement with the experimental enantiomeric elution order and allowed to establish (i) that salt-bridge and H-bond interactions play a pivotal role in the enantiorecognition mechanisms, and (ii) that the π-cation and π-π interactions are the discriminant chemical features between the two SOs in ruling the chiral recognition mechanism. The results of this work clearly demonstrate the high contribution given by MD simulations in the comprehension of the enantiorecognition mechanism with Cinchona alkaloid-based CSPs. However, from this research endeavor it clearly emerged that the MD protocol optimization is crucial for the quality of the produced results. [Display omitted] • The LC enantiorecognition mechanisms were studied by molecular dynamic simulations. • The molecular dynamics protocol was iteratively optimized. • The interactions engaged and energy profiles of the SA-SO associates were monitored. • Analytes were used as chemical probes underlying differences of between the two CSPs. [ABSTRACT FROM AUTHOR]

Chaperonins Hsp60s are required for cellular vitality by assisting protein folding in an ATP-dependent mechanism. Although conserved, the human mitochondrial mHsp60 exhibits molecular characteristics distinct from the E. coli GroEL, with different conformational assembly and higher subunit association dynamics, suggesting a different mechanism. We previously found that the pathological mutant mHsp60V72I exhibits enhanced subunit association stability and ATPase activity. To provide structural explanations for the V72I mutational effects, here we determined a cryo-EM structure of mHsp60V72I. Our structural analysis combined with molecular dynamic simulations showed mHsp60V72I with increased inter-subunit interface, binding free energy, and dissociation force, all contributing to its enhanced subunit association stability. The gate to the nucleotide-binding (NB) site in mHsp60V72I mimicked the open conformation in the nucleotide-bound state with an additional open channel leading to the NB site, both promoting the mutant's ATPase activity. Our studies highlight the importance of mHsp60's characteristics in its biological function. [Display omitted] • The mHsp60 V72I mutation is linked to an increased subunit stability and ATPase activity • Cryo-EM structure and MD simulations explain the observed V72I allostery • Mutant's nucleotide-binding mimics the open conformation found in the NB-bound state • Mutant has a higher binding energy, dissociation force and smaller size than wildtype Syed et al. utilized biochemical characterization, cryo-EM, and molecular dynamics simulation to study the pathological V72I mutation in mitochondrial chaperonin Hsp60. They discovered that this mutation, although not located at the subunit interface or ATP-binding site, enhances subunit association and ATPase activity. [ABSTRACT FROM AUTHOR]

Antibiotic-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Staphylococcus aureus, and Enterobacterales infections are serious global health problems, and class A β-lactamases are one mechanism that leads to antibiotic resistance. QPX7728, relebactam, and enmetazobactam are new β-lactamase inhibitors to combat β-lactam resistance. in silico approach was used in the current study to find which of the three inhibitors would be more effective for all class A β-lactamases and to reveal molecular insights into the differences between their binding energies. The mutations in conserved residues of the active sites of β-lactamases were defined using BLDB and Clustal Omega. FastME and MMseq2 were used for cluster and phylogeny analysis. 3D protein structure models for β-lactamases were built using SWISS-MODEL. ERRAT and Galaxy Web Server were used to verify 42 β-lactamase protein structures. QPX7728, relebactam, and enmetazobactam were docked to β-lactamases by using AutoDock 4.2. The TEM76-relebactam, CTX-M-81-relebactam, TEM-76-enmetazobactam, and CTX-M-200-enmetazobactam complexes were simulated by molecular dynamics method for 500 ns. Based on molecular docking results, relebactam and QPX7728 were more favorable inhibitors for serine A β-lactamases. A 2D representation of the interactions between ligands and β-lactamases showed that S235, hydrogen bonded with TEM-76, might play a role in inhibitor design. A 500-ns MD analysis of complexes indicated that distance from S70, stability in the enzyme active cavity, and high atomic displacement would account for a significant difference in inhibitor binding affinity. [ABSTRACT FROM AUTHOR]

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are bacterial membrane lipids that are ubiquitous in the environment. Although the exact source organism is unknown, the distribution of brGDGTs in mineral soils, peats, and lake sediments is correlated with temperature through a decrease in the degree of methylation with increasing temperature. This empirical observation forms the basis of the brGDGT paleothermometer, one of the most important and widely used organic proxies to reconstruct terrestrial temperatures in the past. However, a mechanistic understanding to underpin this empirical correlation between the degree of methylation of brGDGT lipids and temperature is lacking, hindering a holistic understanding of the brGDGT paleothermometer as well as the membrane dynamics of their bacterial producers. To address this, here we present the first molecular dynamics simulations of membranes consisting of brGDGTs. Using intact polar lipid (IPL) brGDGTs with two sugar headgroups, our simulations demonstrate that increasing the degree of methylation modulates membrane order and packing, rendering the membrane less rigid and more fluid. These results indicate that the empirically observed correlation between the degree of methylation and temperature allows brGDGT-producing bacteria to maintain adequate membrane fluidity. Our simulations provide the first molecular simulation data to support the hypothesis that the brGDGT paleothermometer is based on homeoviscous adaptation. [ABSTRACT FROM AUTHOR]

Lassa hemorrhagic fever, caused by Lassa mammarenavirus (LASV) infection, accumulates up to 5000 deaths every year. Currently, there is no vaccine available to combat this disease. In this study, a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block the α-dystroglycan (α- DG) receptor and prevent LASV influx. Following rigorous absorption, distribution, metabolism, and excretion (ADME) and quantitative structure-activity relationship (QSAR) profiling, molecular docking was conducted with the top ligands against the α-DG receptor. The compounds chrysin, reticuline, and 3-caffeoylshikimic acid emerged as the top three ligands in terms of binding affinity. Post-docking analysis revealed that interactions with Arg76, Asn224, Ser259, and Lys302 amino acid residues of the receptor protein were important for the optimum binding affinity of ligands. Molecular dynamics simulation was performed comprehensively to study the stability of the protein-ligand complexes. In-depth assessment of root-mean-square deviation (RMSD), root mean square fluctuation (RMSF), polar surface area (PSA), B-Factor, radius of gyration (Rg), solvent accessible surface area (SASA), and molecular surface area (MolSA) values of the protein-ligand complexes affirmed that the candidates with the best binding affinity formed the most stable protein-ligand complexes. To authenticate the potentialities of the ligands as target-specific drugs, an in vivo study is underway in real time as the continuation of the research. [ABSTRACT FROM AUTHOR]

The recently discovered carbon honeycombs (CHCs) and boron nitride honeycombs (BNHCs) are found to have the similar molecular structures but different thermal properties. Thus, through appropriately patching together CHCs and BNHCs, the hybrid carbon-boron nitride honeycombs (C–BNHCs) with tunable thermal conductivity can be achieved. In this paper, the machine learning (ML) method together with molecular dynamics simulations is employed to study the thermal transport property of C–BNHCs, and also utilized to design the structures of C–BNHCs for the specific thermal conductivity. Our forward learning study reveals a big difference in the thermal conductivities of C–BNHCs with the same BNHC doping level but different doping arrangements. Meanwhile, a nonmonotonic relation is observed between the thermal conductivity of C–BNHCs and their doping concentration, which, according to our analyses of the phonon density of states and spectral thermal conductivity, is attributed to the complicated phonon scattering behaviors in C–BNHCs. In addition, our ML-based method exhibits the high accuracy and efficiency in the inverse design of C–BNHCs with any specific thermal conductivity. Moreover, as for a target thermal conductivity, the present ML-based inverse design method can output numerous potential optimal structures at once for C–BNHCs, which will greatly shorten the design period of C–BNHCs. [Display omitted] [ABSTRACT FROM AUTHOR]