Molecular Modeling Simulations Research Articles

Current analytical methods and applications used in the insight of serum proteins interactions with various food additives, pesticides, and contaminants

In recent years, many societies have expressed increasing apprehension regarding the potential negative impacts of food additives, pesticides, and environmental contaminants on human health. Environmental or occupational exposure to these compounds can cause significant adverse effects on human health by causing temporary or permanent changes in the immune system. There is supporting evidence linking pesticides/food ingredients/contaminants-induced immune alterations to the prevalence of diseases associated with changes in immune responses. Hence, it is essential to comprehensively understand the key mechanisms contributing to immune dysregulation induced by these substances, including direct immunotoxicity, endocrine disruption, and antigenicity. The impact of pesticides/food ingredients and contaminants on the human body ranges from mild to severe, depending on their affinity for blood components. These compounds form complexes with blood serum proteins, influencing their metabolism, transport, absorption, and overall toxicity. Numerous studies in the literature have explored the interactions between serum proteins and various molecules, including pesticides, drugs, and food dyes. These investigations employed a range of techniques, including spectroscopy, electrochemical and chromatographic methods as well as molecular modeling and molecular dynamics simulations analyses. This recent review, spanning from 2020 to the present, has been employed to investigate the binding characteristics, mechanisms, and attributes of different food additives, pesticides, and contaminants with serum proteins by using various techniques such as steady-state fluorescence, circular dichroism and ultra-violet spectroscopies, and computational docking methods. The review provides insights into these compounds’ positions and affinities to proteins and possible effects on human health through detailed research studies.

Optimization of quenched fluorescent peptide substrates of SARS-CoV-2 3CLpro main protease (Mpro) from proteomic identification of P6-P6' active site specificity.

SARS-CoV-2 3C-like main protease (3CLpro) is essential for protein excision from the viral polyprotein. 3CLpro inhibitor drug development to block SARS-CoV-2 replication focuses on the catalytic non-prime (P) side for specificity and potency, but the importance of the prime (P') side in substrate specificity and for drug development remains underappreciated. We determined the P6-P6' specificity for 3CLpro from >800 cleavage sites that we identified using Proteomic Identification of Cleavage site Specificity (PICS). Cleavage occurred after the canonical P1-Gln and non-canonical P1-His and P1-Met residues. Moreover, P3 showed a preference for Arg/Lys and P3' for His. Essential H-bonds between the N-terminal Ser1 of protomer-B in 3CLpro dimers form with P1-His, but not with P1-Met. Nonetheless, cleavage occurs at P1-Met456 in native MAP4K5. Elevated reactive oxygen species in SARS-CoV-2 infection oxidize methionines. Molecular simulations revealed P1-MetOX forms an H-bond with Ser1 and notably, strong positive cooperativity between P1-Met with P3'-His was revealed, which enhanced peptide-cleavage rates. The highly plastic S3' subsite accommodates P3'-His that displays stabilizing backbone H-bonds with Thr25 lying central in a "'threonine trio" (Thr24-Thr25-Thr26) in the P'-binding domain I. Molecular docking simulations unveiled structure-activity relationships impacting 3CLpro-substrate interactions, and the role of these structural determinants was confirmed by MALDI-TOF-MS cleavage assays of P1'- and P3'-positional scanning peptide libraries carrying a 2nd optimal cut-site as an internal positive control. These data informed the design of two new and highly soluble 3CLproquenched-fluorescent peptide substrates for improved FRET monitoring of 3CLpro activity with 15× improved sensitivity over current assays.IMPORTANCEFrom global proteomics identification of >800 cleavage sites, we characterized the P6-P6' active site specificity of SARS-CoV-2 3CLpro using proteome-derived peptide library screens, molecular modeling simulations, and focussed positional peptide libraries. In P1', we show that alanine and serine are cleaved 3× faster than glycine and the hydrophobic small amino acids Leu, Ile, or Val prevent cleavage of otherwise optimal non-prime sequences. In characterizing non-canonical non-prime P1 specificity, we explored the unusual P1-Met specificity, discovering enhanced cleavage when in the oxidized state (P1-MetOX). We unveiled unexpected amino acid cooperativity at P1-Met with P3'-His and noncanonical P1-His with P2-Phe, and the importance of the threonine trio (Thr24-Thr25-Thr26) in the prime side binding domain I in defining prime side binding in SARS-CoV-2 3CLpro. From these analyses, we rationally designed quenched-fluorescence natural amino acid peptide substrates with >15× improved sensitivity and high peptide solubility, facilitating handling and application for screening of new antiviral drugs.

Effects of RDL GABA Receptor Point Mutants on Susceptibility to Meta-Diamide and Isoxazoline Insecticides in Drosophila melanogaster.

Ionotropic γ-aminobutyric acid (GABA) receptors in insects, specifically those composed of the RDL (resistant to dieldrin) subunit, serve as important targets for commonly used synthetic insecticides. These insecticides belong to various chemical classes, such as phenylpyrazoles, cyclodienes, meta-diamides, and isoxazolines, with the latter two potentially binding to the transmembrane inter-subunit pocket. However, the specific amino acid residues that contribute to the high sensitivity of insect RDL receptors to these novel insecticides remain elusive. In this study, we investigated the susceptibility of seven distinct Drosophila melanogaster Rdl point mutants against four meta-diamide and isoxazoline insecticides: isocycloseram, fluxametamide, fluralaner, and broflanilide. Our findings indicate that, despite exhibiting increased sensitivity to fluralaner in vitro, the RdlI276C mutant showed resistance to isocycloseram and fluxametamide. Similarly, the double-points mutant RdlI276F+G279S also showed decreased sensitivity to the tested isoxazolines. On the other hand, the RdlG335M mutant displayed high levels of resistance to all tested insecticides. Molecular modeling and docking simulations further supported these findings, highlighting similar binding poses for these insecticides. In summary, our research provides robust in vivo evidence supporting the idea that the inter-subunit amino acids within transmembrane M1 and M3 domains form the binding site crucial for meta-diamide and isoxazoline insecticide interactions. This study highlights the complex interplay between mutations and insecticide susceptibility, paving the way for more targeted pest control strategies.

Synergistic shielding of copper from nitric acid corrosion: Unveiling the mechanisms through electrochemical, characterization, and computational insights with 2-Hydroxybenzaldehyde oxime

Schiff-base metallic complexes have garnered considerable attention due to their unique attributes and broad applications across various sectors. Among these, organic Schiff-type bases have emerged as effective agents for mitigating corrosion in challenging environments. This study employs a comprehensive approach to assess the efficiency of 2-Hydroxybenzaldehyde oxime (HOBAO) in preventing copper corrosion. Synthesis and characterization of the HOBAO compound were conducted using FTIR and NMR (1H and 13C) analyses, confirming successful production. The inhibition performance on copper was investigated in a 1 M HNO3 medium utilizing gravimetric, electrochemical impedance spectroscopy, and potentiodynamic polarization techniques. Our findings reveal that HOBAO, at a concentration of 300 ppm, significantly inhibits corrosion, achieving rates of 82.00 %, 93.30 %, and 91.80 % for weight loss, polarization, and EIS analyses, respectively. SEM, EDS, and UV investigations provide evidence of the inhibitor's adsorption onto the copper surface, resulting in a smoother and more uniform appearance with minimal damage. Theoretical and practical results were meticulously compared, demonstrating that HOBAO acts as a mixed-type inhibitor with heightened effectiveness at higher concentrations of 300 ppm. SEM observations offer compelling evidence of inhibitor molecules exhibiting robust resistance against HNO3 attacks at the metal boundaries. Molecular modeling, including DFT and MD simulation studies, further support these findings, suggesting that the oxygen heteroatoms of HOBAO serve as favorable sites for molecular adsorption onto the copper surface. In conclusion, our comprehensive findings highlight HOBAO's potential as a promising copper corrosion inhibitor, particularly in environments containing nitric acid.

Comparative assessment of different anti-CD147/Basigin 2 antibodies as a potential therapeutic anticancer target by molecular modeling and dynamic simulation.

Cluster of differentiation 147 (CD147) is an attractive target for anticancer therapy since it is pivotal in developing and progressing several of malignant tumors in the context of its high expression levels. Although anti-CD147 antibodies by different laboratories are designed for the Ig-like domains of CD147, there is a demand to provide priority among these anti-CD147 antibodies for developing of therapeutic anti-CD147 antibody before experimental validations. This study uses molecular docking and dynamic simulation techniques to compare the binding modes and affinities of nine antibody models against the Ig-like domains of CD147. After obtaining the model antibodies by homology modeling via Robetta, we predicted the CDRs of nine antibodies and the epitopes of CD147 to reach more accurate results for antigen affinity in molecular docking. Next, from HADDOCK 2.4., we meticulously handpicked the most superior model clusters (Z-Score: - 2.5 to - 1.2) and identified that meplazumab had higher affinities according to the success rate as the percentage of a scoring scale. We achieved stable simulations of CD147-antibody interaction. Our outcomes hold hypothetical importance for further experimental cancer research on the design and development of the relevant model antibodies.

The structure, self-assembly and dynamics of lipid nanodiscs revealed by computational approaches

Nanodisc technology is increasingly being used in structural, biochemical and biophysical studies of membrane proteins. The computational approaches have revealed many important features of nanodisc assembly, structures and dynamics. Therefore, we reviewed the application of computational approaches, especially molecular modeling and molecular dyncamics (MD) simulations, to characterize nanodiscs, including the structural models, assembly and disassembly, protocols for modeling, structural properties and dynamics, and protein-lipid interactions in nanodiscs. More amazing computational studies about nanodiscs are looked forward to in the future.

Abstract 4472: Discovery of potential RAF-selective back pocket as a promising biological target for BRAF inhibitors in the treatment of resistant melanoma: Design, synthesis, biological evaluation and in silico studies

Abstract The mutated BRAF kinase (V600E) is considered the key component in the MAPK signaling pathway that was reported to be significantly contributed to melanoma disease. Vemurafenib and dabrafenib are examples of drugs that were approved by FDA to treat melanoma through inhibition of mutated BRAF kinase (V600E). However, drug resistance was reported after 6 - 7 months of treatment using these drugs due to activation of this signaling pathway through another RAF kinase (CRAF). As a Drug Discovery research group, we were interested to study and identify the possible biological target to inhibit this resistant form of cancer. We run molecular modelling simulation to study the key features of the active sites of RAF kinases and we taken vemurafenib as a starting point to design our compounds. We identified a selective back pocket in the active site of RAF kinases that can be targeted to enhance the inhibition of these kinases to overcome the drug resistance in the resistant melanoma. We designed a library of compounds based on imidazothiazole core scaffold decorated with different hydrophobic substituents to target the selectivity back pocket. Among the designed and synthesized series, KS16, that showed potent biological profile against RAF kinases compared to vemurafenib as a standard. In the cellular level, KS16 showed the same potencies against mutated BRAF-based melanoma cell line (A375) as that of vemurafenib. To evaluate the selectivity profile of KS16, kinase panel assay against 60 kinases has been investigated that showed high selectivity profile of KS16 (98 - 100% inhibition against WTBRAF, CRAF and V600EBRAF). In addition, KS16 was submitted to National Cancer Institute (NCI) to be tested against 60 human cancer cell lines in 5-point assay. It showed selective cytotoxic inhibition against melanoma cell lines compared to the other types of cancer cell lines. To evaluate the efficacy of KS16 against resistant melanoma, both KS16 and vemurafenib were tested against resistant melanoma cell line (A375R). The results revealed that KS16 showed the capability to inhibit the growth of resistant melanoma cell line in contrast to vemurafenib which failed to exhibit the same inhibition profile. The drug-candidate cardiac safety profile of KS16 was emphasized in this current project. KS16 was tested against hERG using E4031 (IC50 = 0.025 μM) as positive control to set up the hERG channel binding assay. The results revealed that KS16 showed relatively weak binding to hERG (% inh 64%) compared to that of the potent positive control (E4031, % inh 97%). The results revealed that KS16 is a potential drug candidate with minimal cardiotoxic effect. Further pharmacokinetic studies are being performed to KS16 to investigate and develop the ADME profile of KS16 to be a potential selected drug candidate against resistant melanoma disease. Citation Format: Usama Ammar, Mahmoud Gamal, Mohammed Abdel-Maksoud, Eslam Ali, Zeyad Mahmoud, Kim Deug, Park Jun, Soo Lee, Chang Oh. Discovery of potential RAF-selective back pocket as a promising biological target for BRAF inhibitors in the treatment of resistant melanoma: Design, synthesis, biological evaluation and in silico studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4472.

Mechanistic QSAR modeling derived virtual screening, drug repurposing, ADMET and in-vitro evaluation to identify anticancer lead as lysine-specific demethylase 5a inhibitor

A lysine-specific demethylase is an enzyme that selectively eliminates methyl groups from lysine residues. KDM5A, also known as JARID1A or RBP2, belongs to the KDM5 Jumonji histone demethylase subfamily. To identify novel molecules that interact with the LSD5A receptor, we created a quantitative structure-activity relationship (QSAR) model. A group of 435 compounds was used in a study of the quantitative relationship between structure and activity to guess the IC50 values for blocking LASD5A. We used a genetic algorithm-multilinear regression-based quantitative structure-activity connection model to forecast the bioactivity (PIC50) of 1615 food and drug administration pharmaceuticals from the zinc database with the goal of repurposing clinically used medications. We used molecular docking, molecular dynamic simulation modelling, and molecular mechanics generalised surface area analysis to investigate the molecule’s binding mechanism. A genetic algorithm and multi-linear regression method were used to make six variable-based quantitative structure-activity relationship models that worked well (R 2 = 0.8521, Q 2 LOO = 0.8438, and Q 2 LMO = 0.8414). ZINC000000538621 was found to be a new hit against LSD5A after a quantitative structure-activity relationship-based virtual screening of 1615 zinc food and drug administration compounds. The docking analysis revealed that the hit molecule 11 in the KDM5A binding pocket adopted a conformation similar to the pdb-6bh1 ligand (docking score: −8.61 kcal/mol). The results from molecular docking and the quantitative structure-activity relationship were complementary and consistent. The most active lead molecule 11, which has shown encouraging results, has good absorption, distribution, metabolism, and excretion (ADME) properties, and its toxicity has been shown to be minimal. In addition, the MTT assay of ZINC000000538621 with MCF-7 cell lines backs up the in silico studies. We used molecular mechanics generalise borne surface area analysis and a 200-ns molecular dynamics simulation to find structural motifs for KDM5A enzyme interactions. Thus, our strategy will likely expand food and drug administration molecule repurposing research to find better anticancer drugs and therapies. Communicated by Ramaswamy H. Sarma

Alternative splicing generates a novel ferroportin isoform with a shorter C-terminal and an intact iron- and hepcidin-binding property.

Ferroportin (FPN) is a transmembrane protein and is the only known iron exporter that helps in maintaining iron homeostasis in vertebrates. To maintain stable iron equilibrium in the body, ferroportin works in conjunction with a peptide called hepcidin. In this study, we have identified an alternatively spliced novel isoform of the human SLC40A1 gene, which encodes for the FPN protein and is found to be expressed in different tissues. The novel transcript has an alternate last exon and encodes 31-amino acid long peptide sequence that replaces 104 amino acids at C-terminal in the novel transcript. Molecular modelling and molecular dynamics (MD) simulation studies revealed key structural features of the novel isoform (FPN-N). FPN-N was predicted to have 12 transmembrane domains similar to the reported isoform (FPN), despite being much smaller in size. FPN-N was found to interact with hepcidin, a key regulator of ferroportin activity. Also, the iron-binding sites were retained in the novel isoform as revealed by the MD simulation of FPN-N in bilipid membrane. The novel isoform identified in this study may play important role in iron homeostasis. However, further studies are required to characterize the FPN-N isoform and decipher its role inside the cell.

Structure-activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling.

The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes in these cells and in PDAC animal models. It is currently in Phase 1a clinical evaluation as an anticancer drug. A study of structure-activity relationships of QN-302 and two related analogues (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with molecular modelling and molecular dynamics simulations. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the latter: these two compounds have closely similar transcriptional profiles. Whereas QN-302 (with an additional benzyl-pyrrolidine group), although also showing down-regulatory effects in the same cancer-related pathways, has effects on distinct genes, for example in the hedgehog pathway. This distinctive pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its enhanced ability to stabilize G4 structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a G4 groove compared to the hydrogen atom in CM03 or the methoxy group substituent in SOP1247.

Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.

XRD/DFT, Hirshfeld surface analysis and molecular modelling simulations for unfolding reactivity of newly synthesized vanillin derivatives: excellent optical, NLO and protein binding efficiency

New vanillin derivatives, namely, ethyl (4-formyl-2-methoxyphenoxy)acetate (2a) and 2-(4-formyl-2-methoxyphenoxy)-N-phenylacetamide (2b), respectively, were synthesized and characterized by NMR (1H and 13C), IR, mass spectra and confirmed by single-crystal X-ray analysis. Hirshfeld surface (HS) analysis was performed to probe intra- and intermolecular interactions and surface reactivity. 2D fingerprint plots (FP) were used to study the nature and percentage contribution of intermolecular interactions leading to the formation of the crystal unit. Density functional theory (DFT) simulations were used to obtain the electronic structure and reactivity of the new molecules. Natural population analysis (NPA) and frontier molecular orbital (FMO) calculations reveal significant charge transfer and a reduced HOMO-LUMO gap up to 4.34 eV for 2b. Bader’s quantum theory of atoms in molecules (QTAIM) study is utilized to understand the surface topological and bonding nature of 2a and 2b. The performed molecular electrostatic potential (MESP) and density of states (DOS) study further suggest sites likely to be attractive to incoming reagents. At the same time, hyperpolarizability (βo) is used to characterize the nonlinear optical properties, and TD-DFT study shows the excitation energy and absorption behavior. In silico studies were performed, including docking, binding free energies (MMBGSA) and molecular dynamics simulations. Compounds 2a and 2b were docked with RdRp of SARS-Cov-2, and the MMBGSA for 2a and 2b were −30.70 and −28.47 kcal/mol, respectively, while MD simulation showed the stability of protein-ligand complexes. Communicated by Ramaswamy H. Sarma

Toroid-rod supramolecular polymorphism derived from conformational isomerism of a π-conjugated system.

Hydrogen-bonded supermacrocycles (rosettes) composed of dinaphthylethene π-conjugated systems show unique supramolecular polymorphism affording nanorings and nanorods via kinetically controlled self-assembly. Molecular modeling and molecular dynamics simulations proposed that conformational isomerism of the π-conjugated systems leads to planar and convex rosette geometries, which results in their distinct stacking arrangements.

Functional validation of A2'N mutation of the RDL GABA receptor against fipronil via molecular modeling and genome engineering in drosophila.

Insect RDL (resistant to dieldrin) receptors are essential pentameric ligand-gated chloride channels that mediate the neuroinhibitory effect of GABA, the chief inhibitory neurotransmitter in the central nervous system. These receptors serve as primary targets for various insecticides, including noncompetitive antagonists (NCAs) such as cyclodiene organochlorines and phenylpyrazoles, as well as allosteric modulators like meta-diamides and isoxazolines. This study focuses on a newly discovered A2'N mutation within the RDL receptors, identified in fipronil-resistant planthoppers. Despite in vitro electrophysiological studies have proposed its role in conferring target-site resistance, in vivo genetic functional validation of this mutation remains unexplored. Our research employed toxicity bioassays, assessing various Rdl genotypes against a spectrum of insecticides, including fipronil, α-endosulfan, broflanilide, and isocycloseram. Results revealed distinct resistance profiles for A2'N and A2'S mutants, indicating different binding interactions of RDL receptors with NCAs. Significantly, the A2'N heterozygote showed substantial resistance to fipronil, despite its homozygous lethality. Molecular modeling and docking simulations further supported these findings, highlighting unique binding poses for fipronil and α-endosulfan. This study confirmed that A2'N mutation of the RDL GABA receptor confer high resistance to fipronil in vivo. The observed resistance in A2'N mutants is likely attributable to a steric hindrance mechanism, wherein the introduction of larger side chains hampers fipronil binding, even in a heterozygous state. © 2023 Society of Chemical Industry.

Developing a new multi-featured chitosan-quinoline Schiff base with potent antibacterial, antioxidant, and antidiabetic activities: design and molecular modeling simulation

A new chitosan Schiff base was developed via the reaction of chitosan (CH) with 2-chloro-3-formyl-7-ethoxy quinoline (Q) derivative. The alteration in the chemical structure and morphology of CHQ derivative was confirmed by 1H NMR, FT-IR spectroscopy and SEM analysis. The antibacterial activity was considerably promoted with increasing quinoline concentration up to 1 M with maximal inhibition reached 96 and 77% against Staphylococcus haemolyticus and Escherichia coli, respectively. Additionally, CHQ derivative afforded higher ABTS·+ radical scavenging activity reached 59% compared to 13% for native chitosan, approving its acceptable antioxidant activity. Moreover, the developed CHQ derivative can stimulate the glucose uptake in HepG-2 and yeast cells, while better inhibition of α-amylase and α-glucosidase was accomplished with maximum values of 99.78 and 92.10%, respectively. Furthermore, the molecular docking simulation clarified the binding mode of CHQ derivative inside the active site of α-amylase and α-glucosidase, suggesting its potential use as diabetes mellitus drug. The DFT calculations indicated an improvement in the electronic properties of CHQ with a lower energy band gap reached 4.05eV compared to 5.94eV for CH. The cytotoxicity assay revealed the safety of CHQ towards normal HSF cells, hypothesizing its possible application as non-toxic antibacterial, antioxidant, and antidiabetic agent for biomedical applications.

Molecular interactions between perlecan LG3 and the SARS-CoV-2 spike protein receptor binding domain.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global health crisis with significant clinical morbidity and mortality. While angiotensin-converting enzyme 2 (ACE2) is the primary receptor for viral entry, other cell surface and extracellular matrix proteins may also bind to the viral receptor binding domain (RBD) within the SARS-CoV-2 spike protein. Recent studies have implicated heparan sulfate proteoglycans, specifically perlecan LG3, in facilitating SARS-CoV-2 binding to ACE2. However, the role of perlecan LG3 in SARS-CoV-2 pathophysiology is not well understood. In this study, we investigated the binding interactions between the SARS-CoV-2 spike protein RBD and perlecan LG3 through molecular modeling simulations and surface plasmon resonance (SPR) experiments. Our results indicate stable binding between LG3 and SARS-CoV-2 spike protein RBD, which may potentially enhance RBD-ACE2 interactions. These findings shed light on the role of perlecan LG3 in SARS-CoV-2 infection and provide insight into SARS-CoV-2 pathophysiology and potential therapeutic strategy for COVID-19.

Synthesis, structure elucidation, SC-XRD/DFT, molecular modelling simulations and DNA binding studies of 3,5-diphenyl-4,5-dihydro-1H-pyrazole chalcones

Deoxyribonucleic acid (DNA) acts as the most important intracellular target for various drugs. Exploring the DNA binding interactions of small bioactive molecules offers a structural guideline for designing new drugs with higher clinical efficacy and enhanced selectivity. This study presents the facile synthesis of pyrazoline-derived compounds (4a)-(4f) by reacting substituted chalcones with hydrazine hydrate using formic acid. The structure elucidation of substituted pyrazoline compounds was carried out using 1H-NMR, FT-IR and elemental analyses. While the crystal structures of two compounds (4a) and (4b) have been resolved by single-crystal X-ray diffraction (SC-XRD) analysis. Hirshfeld surface analysis also endorsed their greater molecular stability. Computational calculations at DFT/B3LYP/6-311++G(d,p) were executed to compare the structural properties (bond angle and bond length) and explore reactivity descriptors, frontier molecular orbitals (FMO), Mulliken atomic charges (MAC), molecular electrostatic potential (MEP) and electronic properties. All the compounds were evaluated for DNA binding interactions by UV-Vis spectrophotometric analysis. The results revealed that compounds (4a)-(4f) bind to DNA via non-covalent binding mode having binding constant values ranging from 1.22 × 103 to 6.81 × 104 M−1. The negative values of Gibbs free energy also proved the interaction of studied compounds with DNA as a spontaneous process. The findings of molecular docking simulations depicted that these studied compounds showed significant binding interactions with DNA and these results were consistent with experimental findings. Compound (4b) was concluded as the most potent compound of the series with the highest binding constant (4.95 × 104) and strongest binding affinity (-8.48 kcal/mol). Communicated by Ramaswamy H. Sarma

Performance of thermally conductive NR composites reinforced with stearic acid‐modified microcrystalline cellulose: A combined experimental and molecular dynamic simulation study

AbstractWith 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.

Biological evaluation, molecular modeling and dynamic simulation of IDQ bulk and IDQNPs: Organo nano-bio interface in the medical field

The study aimed to synthesize 7,7-dimethyl-10-aryl,-7,8-dihydro-5H-indeno-[1,2-b]-quinoline-9,11(6H,10H)‑dione nanoparticles (IDQNPs) and to explore their biological activities i.e. anticancer, antioxidant and antibacterial. For this purpose, we prepared IDQNPs in a single non-solvent i.e. water by simple reprecipitation method. These nanoparticles were highly fluorescent organic nanoparticles (FONPs). The DLS measurements detected that 114 nm size of synthesized IDQNPs. A microphotograph taken using field emission scanning electron microscope (FE-SEM) of air-dried nanoparticle film showed nanoflakes with a feathery shape. Moreover, absorption and emission spectroscopy measurements displayed discrete peak of IDQNPs from their bulk molecule. The highly fluorescent IDQNPs ultimately give higher quantum yield compared to parental IDQ. Fluorescent organic nanoflakes are additionally utilized in vitro for anticancer and antimicrobial activity and antioxidant properties. Cytotoxicity of IDQ and IDQNPs were determined on the basis of measurement of in vitro growth inhibition of breast cancer cell lines in 96 well plates by using 5-fluoro uracil as a standard. The in vitro cytotoxicity of the IDQNPs assayed against MCF-7 cell lines showed higher cytotoxicity with the lower IC50 value i.e. 3.94 than IDQ parent indicating their efficiency in killing the cancer cells even at low concentrations. Furthermore, antioxidant and antibacterial activities were done by DPPH 96 well method and well plate diffusion method respectively. IDQNPs showed significant antioxidant property against DPPH radical. The IDQ parent compound and IDQNPs suspension at concentration 5 mg, 10 mg, and 100 µL, 200 µL respectively does not show activity against E. coli and Stap. Aureus. The molecular docking and dynamic simulation study were as done for IDQ bulk material. The finding of our study recommend that IDQNPs is a suitable candidate for preclinical cancer and antioxidant studies. This report may open a new avenue in the medical field and life science.

Analytical fracture toughness model for multiphase epoxy matrices modified by thermoplastic and carbon nanotube/thermoplastic

The introduction of a toughener is considered one of the most effective approaches to address the brittleness of epoxy resins. This paper introduces an analytical model for investigating the Mode-I fracture toughness of modified epoxy resins by including a phase-separating thermoplastic (TP) polymer, polyetherimide (PEI), and the combination of PEI and carbon nanotubes (CNTs). The fracture energy contributions from different toughening mechanisms, identified by the fractographical studies of the modified epoxy resins, were calculated, in which the energy contribution from TP deformation was obtained by molecular dynamics model simulation. The developed fracture toughness model showed satisfactory agreement with the experimental data. In the TP/epoxy binary system, the increase in TP content from 5 to 20 wt% resulted in a rise in the contribution of TP deformation (crack bridging) leading to a commensurate increase in fracture toughness from 33% to 70%. This transformation established TP deformation as the dominant mechanism for crack energy dissipation. In the CNT/TP/epoxy ternary system, from the model, the observed synergy in toughness was attributed to the improved dispersion of nanotubes. The developed analytical model may be used to formulate multiphase toughened resin matrices for optimal fracture toughness.